Alternative titles; symbols
HGNC Approved Gene Symbol: PTEN
SNOMEDCT: 128791005, 254878006, 58037000, 67944007, 716862002; ICD10CM: D32.9;
Cytogenetic location: 10q23.31 Genomic coordinates (GRCh38): 10:87,863,625-87,971,930 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.31 | {Glioma susceptibility 2} | 613028 | Autosomal dominant | 3 |
| {Meningioma} | 607174 | Autosomal dominant | 3 | |
| Cowden syndrome 1 | 158350 | Autosomal dominant | 3 | |
| Lhermitte-Duclos disease | 158350 | Autosomal dominant | 3 | |
| Macrocephaly/autism syndrome | 605309 | Autosomal dominant | 3 | |
| Prostate cancer, somatic | 176807 | 3 |
The PTEN gene encodes a ubiquitously expressed tumor suppressor dual-specificity phosphatase that antagonizes the PI3K signaling pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (summary by Pezzolesi et al., 2007).
As tumors progress to more advanced stages, they acquire an increasing number of genetic alterations. Li et al. (1997) noted that one alteration that occurs at high frequency in a variety of human tumors is loss of heterozygosity (LOH) at 10q23. Although rarely seen in low-grade glial tumors and early-stage prostate cancers, LOH at 10q23 occurs in approximately 70% of glioblastomas (the most advanced form of glial tumor) and approximately 60% of advanced prostate cancers. This pattern of LOH and the finding that wildtype chromosome 10 suppresses the tumorigenicity of glioblastoma cells in mice suggested to Li et al. (1997) that 10q23 encodes a tumor suppressor gene. By mapping of homozygous deletions on 10q23, they isolated a candidate tumor suppressor gene that they called PTEN for 'phosphatase and tensin homolog deleted on chromosome ten.' Sequence analysis of the predicted 403-amino acid open reading frame (ORF) revealed a protein tyrosine phosphatase domain and a large region of homology (approximately 175 amino acids) to chicken tensin (600076; a protein that interacts with actin filaments at focal adhesions) and bovine auxilin. In preliminary screens, Li et al. (1997) detected mutations of PTEN in 31% (13 of 42) of glioblastoma cell lines and xenografts, 100% (4 of 4) of prostate cancer cell lines, 6% (4 of 65) of breast cancer cell lines and xenografts, and 17% (3 of 18) of primary glioblastomas. The homologies displayed by the structure of PTEN suggested to the investigators that it may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
By exon trapping, the same gene was independently isolated by Steck et al. (1997), who designated it MMAC1 (mutated in multiple advanced cancers-1). They began their search for the gene from deletions involving 10q23-q24, which occur in the majority of cases of human glioblastoma multiformes. Homozygous deletions in 4 glioma cells lines further refined the location. The MMAC1 gene spans these deletions and encodes a widely expressed 5.5-kb mRNA with a 403-amino acid ORF. The predicted MMAC1 protein contains sequence motifs with significant homology to the catalytic domain of protein phosphatases and to the cytoskeletal proteins tensin and auxilin. MMAC1 coding-region mutations were observed in a number of glioma, prostate, kidney, and breast carcinoma cell lines or tumor specimens. Steck et al. (1997) also cloned mouse and dog homologs of MMAC1.
Using RT-PCR, Sharrard and Maitland (2000) cloned full-length PTEN and 2 transcripts encoding C-terminally truncated proteins of 345 and 171 amino acids, respectively. All 3 transcripts were expressed in normal lymphocytes and in normal prostatic epithelium cell lines. Glioblastoma and prostate cancer cell lines showed lower and more variable expression.
By comparative genomic analysis in human, mouse, and rat, Pezzolesi et al. (2007) identified a highly conserved sequence upstream of the PTEN promoter with 80% sequence identity. This region contained a canonic E-box sequence (CACGTG) located at position -2181 to -2176, approximately 800 bp upstream of the PTEN core promoter and more than 1.1 kb upstream of its minimal promoter region (located at -958 to -821). In vitro assays suggested that this motif is recognized by members of the basic region-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor family, USF1 (191523) and USF2 (600390). Reporter assays showed that the E-box sequence is involved in mediating PTEN transcriptional activation. Germline deletions involving this region were found in 4 of 30 patients with Cowden syndrome, suggesting that alterations at cis-regulatory elements can contribute to disease pathogenesis.
PTEN Upstream Reading Frame
By examining RNA transcripts in glioblastoma (GBM; 137800) cells, Huang et al. (2021) identified an upstream ORF (uORF) in the 5-prime UTR of the PTEN mRNA. The uORF encodes a 31-amino acid micropeptide, MLDHR (620760), which the authors called MP31. Immunoblot analysis confirmed the presence of endogenous MP31 protein in 293T cells. Knockout of MP31 did not affect PTEN expression. For further information on MLDHR, see 620760.
Crystal Structure
Lee et al. (1999) described the 2.1-angstrom crystal structure of human PTEN bound to L(+)-tartrate. The PTEN structure reveals a phosphatase domain that is similar to protein phosphatases but also has an enlarged active site important for the accommodation of the phosphoinositide substrate. The structure also reveals that PTEN has a C2 domain. The PTEN C2 domain bound phospholipid membranes in vitro, and mutation of basic residues that could mediate this reduced the membrane affinity of PTEN and its ability to suppress the growth of glioblastoma tumor cells. The phosphatase and C2 domains associate across an extensive interface, suggesting that the C2 domain may serve to productively position the catalytic domain on the membrane.
Sharrard and Maitland (2000) showed the PTEN gene contains 9 exons plus a variable exon 5b that is skipped in the major PTEN transcript. The 3-prime end of exon 8 is subject to alternative splicing.
Steck et al. (1997) mapped the PTEN gene to chromosome 10q23.3. Hansen and Justice (1998) mapped the Pten gene to mouse chromosome 19.
Pseudogene
For information on a processed pseudogene of PTEN located on chromosome 9p13.3, see 613531.
In S. cerevisiae, the cdc14 gene is essential for cell cycle progression. Analysis of the cdc14 point of action suggests that the protein acts in late nuclear division, and may play a role in preparation for DNA replication during the subsequent cell cycle. Li et al. (1997) identified PTEN, CDC14A (603504), and CDC14B (603505) as human cdc14 homologs. However, sequence analysis revealed that PTEN is more closely related to a different yeast open reading frame, YNL128W. Plasmids expressing PTEN failed to complement a cdc14 mutant yeast strain. Recombinant PTEN exhibited the kinetic properties of dual-specific phosphatases (see 602038) in vitro.
Li and Sun (1998) showed that PTEN expression potently suppressed the growth and tumorigenicity of human glioblastoma cells. The growth suppression activity of PTEN was mediated by its ability to block cell cycle progression in the G1 phase. The studies suggested that the PTEN tumor suppressor modulates G1 cell cycle progression through negatively regulating the PI3K (see 171834)/Akt (164730) signaling pathway, and that 1 critical target of this signaling process is the cyclin-dependent kinase inhibitor p27(KIP1) (600778).
Hypoxia and growth factors are critical modulators of angiogenesis. By immunoblot analysis, Zundel et al. (2000) determined that expression of wildtype PTEN in a glioblastoma cell line with mutant PTEN blocked hypoxia- and IGF1 (147440)-induced AKT1 phosphorylation and kinase activity. PTEN expression, unlike serum deprivation and hypoxia, failed to completely inhibit DNA synthesis as measured by tritiated-thymidine incorporation. Glioblastoma cell lines were highly resistant to induction of apoptosis by hypoxia, serum deprivation, and irradiation with or without PTEN expression, suggesting the presence of additional antiapoptotic mutations in these tumors. Northern blot analysis showed that PTEN expression blocked the expression of endogenous VEGF (192240), COX1 (176805), PGK1 (311800), and PFK (see, e.g., 610681), hypoxia-inducible genes implicated in angiogenesis. In contrast to AKT, PTEN expression also completely suppressed the stabilization of HIF1A (603348) by hypoxia. Zundel et al. (2000) proposed that loss of PTEN contributes to tumor expansion through the deregulation of AKT activity and HIF1-regulated gene expression.
Dahia et al. (1999) analyzed PTEN in a series of primary acute leukemias and non-Hodgkin lymphomas (NHLs) as well as in cell lines. The majority of cell lines studied carried PTEN abnormalities: 40% carried mutations or hemizygous deletions. One-third of cell lines had low PTEN transcript levels, and 60% of these had low or absent PTEN protein. A smaller number of primary hematologic malignancies, in particular NHLs, carried PTEN mutations. PTEN and phosphorylated Akt levels were inversely correlated in the large majority of examined samples, suggesting that PTEN regulates phosphatidylinositol 3,4,5-triphosphates and may play a role in apoptosis.
Tamura et al. (1998) found that overexpression of PTEN inhibited cell migration, whereas antisense PTEN enhanced migration. Integrin-mediated cell spreading and the formation of focal adhesions were downregulated by wildtype PTEN but not by PTEN with an inactive phosphatase domain. PTEN interacted with the focal adhesion kinase FAK (600758) and reduced its tyrosine phosphorylation. Overexpression of FAK partially antagonized the effects of PTEN. Thus, PTEN phosphatase may function as a tumor suppressor by negatively regulating cell interactions with the extracellular matrix.
Cantley and Neel (1999) reviewed the reports indicating that PTEN negatively controls the PI3K signaling pathway for regulation of cell growth and survival by dephosphorylating the 3 position of phosphoinositides.
Gimm et al. (2000) studied the temporal and spatial pattern of PTEN expression during human development using a specific monoclonal antibody. They observed mainly high-level PTEN expression in tissues (e.g., skin, thyroid, and central nervous system) known to be involved in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (CWS1; 158350). In addition, expression was noted in peripheral nervous system, autonomic nervous system, and upper gastrointestinal tract.
Mutter et al. (2000) examined PTEN expression in normal human endometrium during response to changing physiologic levels of steroid hormones. PTEN RNA levels, assessed by RT-PCR, increased several fold in secretory compared to proliferative endometrium. Early in the menstrual cycle under the dominant influence of estrogens, the proliferative endometrium showed ubiquitous cytoplasmic and nuclear PTEN expression. By the midsecretory phase, epithelial PTEN was exhausted, but increased dramatically in the cytoplasm of stromal cells undergoing decidual change. The authors concluded that stromal and epithelial compartments contribute to the hormone-driven changes in endometrial PTEN expression and that abnormal hormonal conditions may, in turn, disrupt normal patterns of PTEN expression in this tissue.
Stambolic et al. (2001) investigated the human genomic PTEN locus and identified a p53 (191170)-binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wildtype p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts.
Di Cristofano and Pandolfi (2000) reviewed the multiple roles of PTEN in tumor suppression.
Weng et al. (1999) demonstrated that overexpression of PTEN in MCF-7 breast cancer cells causes G1 arrest followed by cell death. Weng et al. (2001) demonstrated increased PTEN-mediated cell death of MCF-7 breast cancer cells cultured in low levels of growth factors. The caspase-9 (602234)-specific inhibitor ZVAD blocked PTEN-induced cell death without altering the effect of PTEN on cell cycle distribution. Overexpression of dominant-negative Akt (164730), a downstream protein kinase, induced more cell death but had less effect on the cell cycle than overexpression of PTEN. The authors suggested that in MCF-7 breast cancer cells, the apoptotic cells induced by the overexpression of PTEN are not derived from the G1-arrested cells. Further, they hypothesized that the effect of PTEN on cell death is mediated through the PI3K/Akt pathway, whereas PTEN-mediated cell cycle arrests depend on both PI3K/Akt-dependent and -independent pathways.
By yeast 2-hybrid and deletion analyses, Wu et al. (2000) found that the C-terminal TKV sequence of PTEN interacted with PDZ domain 2 of MAGI3 (615943). Wildtype PTEN, but not TKV-mutant PTEN, coprecipitated with MAGI3 in cotransfected HEK293 cells. MAGI3 enhanced the ability of PTEN to regulate AKT kinase activity, particularly under conditions of low PTEN expression.
Among 10 thyroid cancer cell lines, Weng et al. (2001) found a single follicular thyroid carcinoma (FTC; 188470) line with a hemizygous PTEN deletion and a splice variant in the remaining allele. Four lines, including the FTC line, expressed PTEN mRNA at low levels. Transient expression of PTEN in 7 thyroid cancer cell lines resulted in G1 arrest in 2 well-differentiated papillary thyroid cancer lines (PTCs), and both G1 arrest and cell death in the remaining 5 lines, consisting of 3 FTCs, 1 poorly differentiated PTC, and 1 undifferentiated thyroid cancer. The level of phosphorylated Akt was inversely correlated with the endogenous level of PTEN protein, and overexpression of PTEN blocked Akt phosphorylation in all cells analyzed. The authors suggested that downregulation of PTEN expression at the mRNA level may play a role in PTEN inactivation in thyroid cancer, and that PTEN may exert its tumor-suppressive effect on thyroid cancer through the inhibition of cell cycle progression alone, or both cell cycle progression and cell death.
Weng et al. (2001) further demonstrated that overexpression of wildtype PTEN leads to the suppression of cell growth through the blockade of cell cycle progression, an increase in the abundance of p27 (600778), a decrease in the protein levels of cyclin D1 (168461), and the inhibition of Akt phosphorylation. In contrast, expression of the phosphatase-dead mutation cys124 to ser (C124S; 601728.0023) promoted cell growth and had the opposite effect on the abundance of p27, cyclin D1 levels, and the phosphorylation of Akt. The gly129-to-glu mutation (G129E; 601728.0001), which retains only protein phosphatase activity, behaved like C124S except that the former caused decreased cyclin D1 levels similar to wildtype PTEN. The authors concluded that PTEN exerts its growth suppression through lipid phosphatase-dependent and -independent activities and, most likely, via the coordinate effect of both protein phosphatase and lipid phosphatase activities.
In another study, Weng et al. (2001) showed that PTEN appears to play a unique role in the insulin signaling pathway in a breast cancer model. Ectopic expression of wildtype PTEN in epithelial breast cancer cells resulted in universal inhibition of Akt phosphorylation in response to stimulation by diverse growth factors and selective inhibition of MEK (600982)/extracellular signal-regulated kinase (ERK; 600997) phosphorylation stimulated by insulin (176730) or insulin-like growth factor 1 (IGF1; 147440). The latter was accompanied by a decrease in the phosphorylation of insulin receptor substrate-1 (IRS1; 147545) and the association of IRS1 with Grb2 (108355)/Sos (182530), without affecting the phosphorylation status of the insulin receptor and Shc (600560), nor Shc/Grb2 complex formation. The MEK inhibitor PD980059, but not the PI3K inhibitor wortmannin, abolished the effect of PTEN on insulin-stimulated cell growth. The authors hypothesized that PTEN may block MAPK phosphorylation in response to insulin stimulation by inhibiting the phosphorylation of IRS1 and IRS1/Grb2/Sos complex formation, which may lead to downregulation of cyclin D1, inhibition of cell cycle progression, and suppression of cell growth.
Mutation in the PTEN gene accompanies progression of brain tumors from benign to the most malignant forms. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of angiogenesis, a process termed the angiogenic switch. Wen et al. (2001) reported data indicating that PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals.
Wishart et al. (2001) reviewed PTEN and myotubularin (300415) phosphoinositide phosphatases. Phosphoinositides play an integral role in a diverse array of cellular signaling processes. Although considerable effort has been directed toward characterizing the kinases that produce inositol lipid second messengers, the study of phosphatases that oppose these kinases had been limited. Research has been focused on the identification of novel lipid phosphatases such as PTEN and myotubularin, their physiologic substrates, signaling pathways, and links to human diseases. Wishart et al. (2001) pointed out the usefulness of bioinformatics in conjunction with genetic analyses in model organisms in the elucidation of roles of these enzymes in regulating phosphoinositide-mediated cellular signaling.
Shallow gradients of chemoattractants, sensed by G protein-linked signaling pathways, elicit localized binding of PH domains specific for PI(3,4,5)P3 at sites on the membrane where rearrangements of the cytoskeleton and pseudopod extension occur. Iijima and Devreotes (2002) showed that disruption of PTEN in Dictyostelium discoideum dramatically prolonged and broadened the PH domain relocation and actin polymerization responses, causing the cells lacking PTEN to follow a circuitous route toward the attractant. Exogenously expressed PTEN-GFP localized to the surface membrane at the rear of the cell. Membrane localization required a putative PI(4,5)P2-binding motif and was required for chemotaxis. These results suggested that specific phosphoinositides direct actin polymerization to the leading edge of the cell and that regulation of PTEN plays a critical role in gradient sensing and directional migration.
Funamoto et al. (2002) investigated the mechanisms of leading edge formation in chemotaxing Dictyostelium cells. They demonstrated that while PI3K transiently translocated to the plasma membrane in response to chemoattractant stimulation and to the leading edge in chemotaxing cells, PTEN, a negative regulator of PI3K pathways, exhibited a reciprocal pattern of localization. By uniformly localizing PI3K along the plasma membrane, Funamoto et al. (2002) showed that chemotaxis pathways were activated along the lateral sides of cells and that PI3K could initiate pseudopod formation, providing evidence for a direct instructional role of PI3K in leading edge formation. These findings provided evidence that differential subcellular localization and activation of PI3K and PTEN is required for proper chemotaxis.
Vaults are large cytoplasmic ribonucleoproteins composed largely of MVP (605088) and vault RNA (VTRNA1-1; 612695). Using a yeast 2-hybrid screen, Yu et al. (2002) showed that PTEN interacted with MPV. Endogenous PTEN associated with vault particles isolated from HeLa cells. Coimmunoprecipitation analysis confirmed the interaction between PTEN and MVP. Deletion analysis mapped the interacting regions to the C2 domain of PTEN and the EF-hand motifs of MVP. The interaction was independent of tyrosine phosphorylation, but required calcium, consistent with a calcium-induced conformational change in the MVP EF-hand motifs.
Waite and Eng (2002) provided a comprehensive review of PTEN and discussed the concept of the PTEN hamartoma-tumor syndrome (PHTS). They reviewed data that led them to conclude that juvenile polyposis syndrome (174900) is not a PHTS.
By analyzing PTEN-deficient tumor cell lines, Nakamura et al. (2000) determined that PTEN deficiency leads to aberrant localization of FKHR (136533) to the cytoplasm. Restoration of PTEN expression restored FKHR to the nucleus and restored transcriptional activation. The authors found evidence that FKHR is an effector of PTEN-associated functions, in that FKHR induced apoptosis in cells that undergo PTEN-mediated apoptosis, and FKHR mediated G1 arrest in cells that undergo PTEN-mediated cell cycle arrest.
Modur et al. (2002) found that both FKHR and FKHRL1 (602681) were highly expressed in normal prostate. They also noted that, in a PTEN-deficient prostate carcinoma cell line, FKHR and FKHRL1 were cytoplasmically sequestered and inactive, and expression of TRAIL (603598), a proapoptotic effector, was decreased. Modur et al. (2002) determined that TRAIL is a direct target of FKHRL1, and they hypothesized that the loss of PTEN contributes to increased tumor cell survival through decreased transcriptional activity of FKHR and FKHRL1 followed by decreased TRAIL expression and apoptosis.
Weng et al. (2002) demonstrated that overexpression of wildtype PTEN in the MCF-7 breast cancer line resulted in a phosphatase activity-dependent decrease in the phosphorylation of ETS2 (164740), a transcription factor whose DNA-binding ability is controlled by phosphorylation. Exposure of MCF-7 cells to insulin, IGF1, epidermal growth factor (EGF; 131530) can lead to the phosphorylation of ETS2. The MEK (MAP2K1; 176872) inhibitor PD590089 abrogated insulin-stimulated phosphorylation of ETS2. In contrast, the PI3K inhibitor LY492002 had no effect on insulin-stimulated phosphorylation of ETS2. Overexpression of PTEN abrogated activation of the uPA Ras-responsive enhancer (PLAU1; 191840), a target of ETS2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. The authors suggested that PTEN may block insulin-stimulated ETS2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS2 may be mediated through PTEN's protein phosphatase activity.
Germline mutations in BMPR1A (601299), the gene encoding the type 1A receptor of bone morphogenetic proteins (BMP), have been found in rare families with Cowden syndrome, or Cowden-like syndrome (601299.0005), suggesting that there may be a link between BMP signaling and PTEN. Waite and Eng (2003) found that exposure to BMP2 (112261) increased PTEN protein levels in the breast cancer cell line MCF-7. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, suggesting that BMP2 stimulation inhibited PTEN protein degradation. BMP2 treatment of MCF-7 cells decreased the association of PTEN with 2 proteins in the degradative pathway, UBE2L3 (603721) and UBE2E3 (604151). The authors suggested that BMP2 exposure may regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway, which may explain how BMPR1A may act as a minor susceptibility gene for PTEN-mutation-negative Cowden syndrome.
Goberdhan and Wilson (2003) reviewed the functions of PTEN.
Inactivation of PTEN and overexpression of VEGF are 2 of the most common events observed in high-grade malignant gliomas (see 137800). Gomez-Manzano et al. (2003) showed that transfer of PTEN to glioma cells under normoxic conditions decreased the level of secreted VEGF protein by 42 to 70% at the transcriptional level. Assays suggested that PTEN acts on VEGF most likely via downregulation of the transcription factor HIF1-alpha and by inhibition of PI3K. Increased PTEN expression also inhibited the growth and migration of glioma-activated endothelial cells in culture.
Raftopoulou et al. (2004) demonstrated that PTEN inhibits cell migration through its C2 domain, independent of its lipid phosphatase activity. This activity depends on the protein phosphatase activity of PTEN and on the dephosphorylation at a single residue, threonine-383. Raftopoulou et al. (2004) suggested that the ability of PTEN to control cell migration through its C2 domain is likely to be an important feature of its tumor suppressor activity.
Nagata et al. (2004) showed that PTEN not only antagonizes tumorigenesis but also sensitizes breast cancers to targeted therapy with trastuzumab (Herceptin), a humanized monoclonal antibody against ERBB2 (164870). The authors provided data that clarified the antitumoral mechanism of trastuzumab and helped clarify the mechanism underlying resistance. They showed that, on binding to the ERBB2 receptor, trastuzumab stabilizes and activates the PTEN tumor suppressor and consequently downregulates the PI3K/Akt signaling pathway. When the expression of PTEN is reduced or abrogated, this chain of events is interrupted and the antitumoral effects of trastuzumab are impaired. Nagata et al. (2004) confirmed, in a small group of patients, that the presence of low levels of PTEN correlated with unresponsiveness to trastuzumab treatment. Pandolfi (2004) discussed ways to make use of this information with drugs that augment PTEN levels and other strategies.
By yeast 2-hybrid screening, in vitro protein binding assays with recombinant proteins, and coimmunoprecipitation of endogenous proteins, Okahara et al. (2004) demonstrated a direct interaction between the C-terminal domain of PTEN and GLTSCR2 (605691). The interaction required amino acids 338 through 348 of GLTSCR2 and a C-terminal segment of PTEN that did not include the PDZ domain. Downregulation of GLTSCR2 in breast carcinoma cells by RNA interference enhanced the degradation of PTEN with concomitant decrease in PTEN phosphorylation. PTEN C-terminal tumor-associated mutants, which are highly susceptible to protein degradation, were unable to bind GLTSCR2 and showed reduced phosphorylation. Okahara et al. (2004) concluded that GTSCR2 interacts directly with PTEN and promotes its phosphorylation and stability.
Sanchez et al. (2005) found that the inhibitory effect of sphingosine 1-phosphate (S1P) on mammalian cell migration required PTEN as a signaling intermediate downstream of EDG5 (605111) and Rho GTPase activation. S1P activation of EDG5 stimulated complex formation between EDG5 and PTEN in the membrane compartment, and EDG5 signaling increased PTEN phosphorylation and its phosphatase activity in membrane fractions. Sanchez et al. (2005) concluded that EDG5 regulates PTEN by a Rho GTPase-dependent pathway to inhibit cell migration.
Chen et al. (2005) showed that conditional inactivation of Trp53 (191170) in the mouse prostate failed to produce a tumor phenotype, whereas complete Pten inactivation in the prostate triggered nonlethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicited invasive prostate cancer as early as 2 weeks after puberty and was invariably lethal by 7 months of age. Importantly, acute Pten inactivation induced growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which could be fully rescued by combined loss of Trp53. In addition, Chen et al. (2005) detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Chen et al. (2005) concluded that their results demonstrated the relevance of cellular senescence in restricting tumorigenesis in vivo and supported a model for cooperative tumor suppression in which p53 is an essential failsafe protein of Pten-deficient tumors.
In MCF7 human breast cancer cells, Waite et al. (2005) showed that stimulation with phytoestrogens, such as resveratrol, quercetin and genistein, resulted in an increase in PTEN protein levels. Phytoestrogen stimulation also resulted in decreased Akt1 (164730) phosphorylation and an increase in p27 (CDKN1B; 600778) protein levels, indicating active PTEN lipid phosphatase activity. In contrast, MAPK1 (176948) phosphorylation and cyclin D1 (CCND1; 168461) levels, which are regulated by PTEN activity, were not altered. PTEN mRNA levels were slightly increased in cells stimulated by phytoestrogens, suggesting that the mechanism for increased PTEN protein expression may be dependent upon transcription. Waite et al. (2005) hypothesized that a mechanism for the protective effect of phytoestrogens against breast cancer may be partially through increased PTEN expression.
Valiente et al. (2005) showed that the C-terminal tail of human PTEN bound to the PDZ domains of rat Magi2 (606382), Magi3, and Dlg (DLG1; 601014), mouse Sast (MAST1; 612256) and Mast205 (MAST2; 612257), and human MAST3 (612258). Interaction of PTEN with Magi2 increased PTEN protein stability, and interaction of PTEN with the MAST kinases facilitated phosphorylation of PTEN by these kinases.
Mehenni et al. (2005) identified PTEN as an LKB1 (STK11; 602216)-interacting protein. Several LKB1 point mutations associated with Peutz-Jeghers syndrome (PJS; 175200) disrupted the interaction with PTEN, suggesting that loss of this interaction might contribute to PJS. Although PTEN and LKB1 are predominantly cytoplasmic and nuclear, respectively, their interaction led to a cytoplasmic relocalization of LKB1. PTEN was found to be a substrate of the kinase LKB1 in vitro. As PTEN is a dual phosphatase mutated in autosomal inherited disorders with phenotypes similar to those of PJS, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS)/Cowden disease (158350), Mehenni et al. (2005) suggested a functional link between the proteins involved in different hamartomatous polyposis syndromes and emphasized the central role played by LKB1 as a tumor suppressor in the small intestine.
Agrawal et al. (2005) characterized the transcriptional and biochemical outcomes of 5 distinct splice site mutations in the PTEN gene, leading to the skipping of exon 3, 4, or 6, among patients with classic CS/BRRS, and CS- or BRRS-like features. The splice site mutations leading to the deletion of exon 3, 4, or 6 resulted in reduced dual phosphatase activities of PTEN. Deletion of exon 4 was associated with severely reduced lipid phosphatase activity, whereas exon 3 skipping resulted in markedly reduced protein phosphatase activity. In addition, exon 3 deleted transcript and protein were stable and localized to the nucleus more efficiently than the wildtype PTEN. In contrast, exon 4 skipping resulted in unstable transcripts and severely truncated unstable PTEN protein lacking its phosphatase domain.
Yilmaz et al. (2006) conditionally deleted the Pten tumor suppressor gene in adult hematopoietic cells. This led to myeloproliferative disease within days and transplantable leukemias within weeks. Pten deletion also promoted hematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR (601231) as they were inhibited by rapamycin. Rapamycin not only depleted leukemia-initiating cells but also restored normal HSC function. Yilmaz et al. (2006) concluded that mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.
Zhang et al. (2006) showed that inactivation of Pten in bone marrow HSCs causes their short-term expansion but long-term decline, primarily owing to an enhanced level of HSC activation. Pten-deficient HSCs engrafted normally in recipient mice, but had an impaired ability to sustain hematopoietic reconstitution, reflecting the dysregulation of their cell cycle and decreased retention in the bone marrow niche. Mice with Pten-mutant bone marrow also had an increased representation of myeloid and T-lymphoid lineages and developed myeloproliferative disorder. Notably, the cell populations that expanded in PTEN mutants matched those that become dominant in the acute myeloid/lymphoid leukemia that develops in later stages of myeloproliferative disorder (MPD). Thus, Zhang et al. (2006) concluded that PTEN has essential roles in restricting the activation of HSCs, in lineage fate determination, and in the prevention of leukemogenesis.
Zhao et al. (2006) showed that electric fields, of a strength equal to those detected endogenously, direct cell migration during wound healing as a prime directional cue. Manipulation of endogenous wound electric fields affects wound healing in vivo. Electric stimulation triggers activation of Src and inositol-phospholipid signaling, which polarizes in the direction of cell migration. Notably, genetic disruption of phosphatidylinositol-3-hydroxykinase gamma (PIK3CG; 601232) decreased electric field-induced signaling and abolished directed movements of healing epithelium in response to electric signals. Deletion of PTEN enhanced signaling and electrotactic responses. Zhao et al. (2006) concluded that their data identified genes essential for electrical signal-induced wound healing and showed that PIK3CG and PTEN control electrotaxis.
Okumura et al. (2006) showed that PCAF (602303), a histone acetyltransferase that regulates gene transcription, interacted physically and functionally with PTEN. PCAF acetylated PTEN on lys125 and lys128 within the catalytic cleft essential for phosphoinositol phosphate specificity, and this acetylation depended on the presence of growth factors. Reduction of endogenous PCAF in human embryonic kidney cells using short hairpin RNA resulted in loss of PTEN acetylation in response to growth factors, and restored PTEN- mediated downregulation of PI3K signaling and induction of G1 cell cycle arrest. Acetylation-resistant PTEN mutants retained the ability to regulate PI3K and induce cell cycle arrest following PCAF overexpression.
Takahashi et al. (2006) found that PTEN interacted with NHERF1 (SLC9A3R1; 604990) and NHERF2 (SLC9A3R2; 606553) adaptor proteins. A ternary complex was formed between PTEN, NHERF proteins and PDGFR (see PDGFRA; 173490), resulting in activation of the PI3K pathway upon PDGF (see PDGFA; 173430) binding. In Nherf1 -/- mouse embryonic fibroblasts, activation of the PI3K pathway by Pdgfr was prolonged in comparison with wildtype cells, consistent with defective Pten recruitment to Pdgfr in the absence of Nherf1. Depletion of Nherf2 by small interfering RNA similarly increased PI3K signaling. Loss of Nherf1 enhanced Pdgf-induced cytoskeletal rearrangements and chemotactic migration. Takahashi et al. (2006) concluded that NHERF proteins recruit PTEN to PDGFR to restrict PI3K activation.
In studies in human astrocytes engineered to contain alterations functionally equivalent to those seen in human malignant glioma, Parsa et al. (2007) demonstrated that expression of the PDCD1LG1 gene (605402) increased posttranscriptionally after loss of PTEN and activation of the PI3K pathway. Levels of B7H1, the PDCD1LG1 gene product, correlated with PTEN loss in glioblastoma specimens, and tumor-specific T cells lysed human glioma targets expressing wildtype PTEN more effectively than those expressing mutant PTEN. Parsa et al. (2007) concluded that immunoresistance in glioma is related to loss of the tumor suppressor PTEN and is mediated in part by B7H1.
Some T-cell acute lymphoblastic leukemias (T-ALL) show resistance to gamma-secretase inhibitors, which act by blocking NOTCH1 (190198) activation. Using microarray analysis, Palomero et al. (2007) identified PTEN as the gene most consistently downregulated in gamma-secretase inhibitor-resistant T-cell lines. Further analysis showed that these resistant cell lines had truncating mutations in the PTEN gene. Loss of PTEN function resulted in aberrant activation of the PI3-kinase-AKT signaling pathway, which induced resistance to gamma-secretase inhibitors. Studies in normal mouse thymocytes indicated that Notch1 regulated Pten expression downstream. Notch signaling and the PI3-kinase-AKT pathway acted synergistically in a Drosophila model of Notch-induced tumorigenesis. The findings demonstrated that NOTCH1 controls a transcriptional network that regulates PTEN expression and PI3-kinase-AKT signaling activity in normal thymocytes and leukemic T cells.
Mazurek et al. (2007) showed that introduction of phosphorylated GAL3 (LGALS3; 153619) into a GAL3-null human breast cancer cell line promoted apoptotic cell death through TRAIL (TNFSF10; 603598), a member of the tumor necrosis factor family that transmits death signals through death domain-containing receptors. Downstream, TRAIL sensitivity depended upon induction of PTEN expression and inactivation of the PI3K/AKT survival pathway.
Using protein pull-down assays, Wang et al. (2007) showed that PTEN interacted directly with endogenous NEDD4 (602278) in human embryonic kidney cells. NEDD4, an E3 ubiquitin ligase, polyubiquitinated PTEN and negatively regulated its stability.
Trotman et al. (2007) found that monoubiquitination of PTEN permitted its shuttling to nuclei, while polyubiquitination led to cytoplasmic retention and degradation. They further found that lys289 and lys13 were targets for ubiquitination, and their mutation led to a constitutive shuttling defect that was overcome by forced monoubiquitination. Knockdown of NEDD4 in human or mouse cells led to cytoplasmic and/or perinuclear accumulation of PTEN, suggesting that NEDD4 is required for PTEN monoubiquitination. Nuclear PTEN retained its ability to antagonize AKT and cause apoptosis. Trotman et al. (2007) concluded that retention of nuclear import capability of PTEN is critical for its tumor-suppressive effects.
Drinjakovic et al. (2010) showed that Pten opposed arborization of retinal ganglion cell axonal projections to the tectum in developing Xenopus embryos. Proteasomal degradation of Pten via Nedd4, and possibly netrin-1 (NTN1; 601614), was required to permit arborization.
Using wildtype and Pten-defective mouse embryonic fibroblasts, Shen et al. (2007) showed that nuclear Pten was essential to maintain chromosome integrity. Pten localized at centromeres and associated directly with Cenpc (117140), an integral component of kinetochores. Loss of Pten led to extensive centromere breakage and defects in DNA double-strand break repair. Pten regulated Rad51 (179617) at the transcriptional level, thus contributing to chromosome stability.
Alvarez-Breckenridge et al. (2007) found that overexpression of PTEN in a human breast cancer cell line increased phospholipase D (see 602382) activity, resulting in increased phosphatidic acid and decreased phosphatidylcholine. They hypothesized that PTEN modulates PLC (see PLCG1; 172420)-PLD activation pathways, in addition to activating the AKT pathway.
Formation of the apical surface and lumen is a fundamental step in epithelial organ development. Martin-Belmonte et al. (2007) showed that Pten localized to the apical plasma membrane during epithelial morphogenesis to mediate enrichment of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) at this domain during cyst development in a 3-dimensional Madin-Darby canine kidney cell system. Ectopic PtdIns(4,5)P2 at the basolateral surface caused apical proteins to relocalize to the basolateral surface. Annexin-2 (ANX2; 151740) bound PtdIns(4,5)P2 and was recruited to the apical surface. Anx2 bound Cdc42 (116952) and recruited it to the apical surface, and Cdc42 in turn recruited the Par6 (607484)/atypical protein kinase C (aPKC; see 176982) complex to the apical surface. Loss of function of Pten, Anx2, Cdc42, or aPKC prevented normal development of the apical surface and lumen. Martin-Belmonte et al. (2007) concluded that PTEN, PtdIns(4,5)P2, ANX2, CDC42, and aPKC control apical plasma membrane and lumen formation.
Mao et al. (2008) demonstrated that mTOR (601231) is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7 (606278). Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN, which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, suggesting to Mao et al. (2008) that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.
Song et al. (2008) found that PTEN was aberrantly localized in acute promyelocytic leukemia (APL; 612376) in which PML (102578) function was disrupted by the PML-RARA (180240) fusion oncoprotein. Treatment with drugs that triggered PML-RARA degradation restored nuclear PTEN. PML opposed the activity of HAUSP (USP7; 602519) towards PTEN through a mechanism involving DAXX (603186). Confocal microscopy and immunohistochemistry demonstrated that HAUSP was overexpressed in prostate cancer and that levels of HAUSP directly correlated with tumor aggressiveness and with PTEN nuclear exclusion. Song et al. (2008) concluded that a PML-HAUSP network controls PTEN deubiquitinylation and subcellular localization, which is perturbed in human cancers.
Zheng et al. (2008) showed that concomitant central nervous system-specific deletion of p53 (191170) and Pten in the mouse central nervous system generates a penetrant acute-onset high grade malignant glioma phenotype with notable clinical, pathologic, and molecular resemblance to primary glioblastoma in humans. This genetic observation prompted TP53 and PTEN mutation analysis in human primary glioblastoma, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis, and functional studies of murine neural stem cells established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc (190080) protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of neural stem cells doubly null for p53 and Pten (p53-/-Pten-/-) as well as tumor neurospheres derived from this model. Myc also serves to maintain robust tumorigenic potential of p53-/-Pten-/- tumor neurospheres. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary glioblastoma, validated a pathogenetic role of a common tumor suppressor mutation profile in human primary glioblastoma and established Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal, and tumorigenic potential.
To test for the role of intrinsic impediments to axon regrowth, Park et al. (2008) analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN, a negative regulator of the mTOR pathway, in adult retinal ganglion cells promoted robust axon regeneration after optic nerve injury. In wildtype adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized retinal ganglion cells, which may have contributed to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex-1 (TSC1; 605284), another negative regulator of the mTOR pathway, also led to axon regeneration.
Using immunohistochemical analysis, Kim et al. (2008) found that Pten was highly expressed in mouse retinal pigment epithelium (RPE) and in retinal ganglion cell axons. RPE-specific deletion of Pten resulted in RPE cells that failed to maintain basolateral adhesions, underwent epithelial-to-mesenchymal transition (EMT), and subsequently migrated out of the retina entirely, leading to progressive death of photoreceptors. Mutation analysis showed that the C-terminal PDZ-binding domain of Pten was essential for maintenance of RPE cell junctional integrity. Inactivation of Pten, and loss of its interaction with junctional proteins, were also evident in RPE cells isolated from Ccr2 (601267) -/- mice and from mice subjected to oxidative damage, both of which displayed age-related macular degeneration. Kim et al. (2008) concluded that PTEN has an essential role in normal RPE cell function and in the response of these cells to oxidative stress.
Using reporter gene assays and Western blot analysis, Ma et al. (2008) found that CSIG (RSL1D1; 615874) negatively regulated PTEN and its downstream effector p27(KIP1), both of which are required for replicative senescence. Binding studies showed that CSIG interacted with a specific segment of the PTEN 5-prime UTR, possibly indirectly, and downregulated PTEN translation, resulting in p27(KIP1) destabilization. Expression of PTEN was essential for CSIG-dependent expression of p27(KIP1) and cell cycle progression.
Kalaany and Sabatini (2009) showed that certain human cancer cell lines, when grown as tumor xenografts in mice, are highly sensitive to the antigrowth effects of dietary restriction, whereas others are resistant. Cancer cell lines that form dietary restriction-resistant tumors carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K; see PIK3CA, 171834) pathway and in culture proliferate in the absence of insulin (176730) or insulin-like growth factor-1 (IGF1; 147440). Substitution of an activated mutant allele of PIK3CA with wildtype PIK3CA in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, was sufficient to convert a dietary restriction-resistant tumor into one that was dietary restriction-sensitive. Dietary restriction did not affect a PTEN-null mouse model of prostate cancer, but it significantly decreased tumor burden in a mouse model of lung cancer lacking constitutive PI3K signaling. Kalaany and Sabatini (2009) concluded that the PI3K pathway is an important determinant of the sensitivity of tumors to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies. Kalaany and Sabatini (2009) also found that overexpression of FOXO1 (136533) sensitizes tumors to dietary restriction.
Huse et al. (2009) showed that MIR26A (see MIR26A2; 613057) is a direct regulator of PTEN expression. MIR26A was overexpressed in a subset of high-grade gliomas, primarily due to amplification of the MIR26A2 locus, a genomic event strongly associated with monoallelic PTEN loss. In a mouse glioma model Mir26a reduced Pten levels, facilitating glioma formation. Mir26a overexpression functionally substituted for loss of heterozygosity at the Pten locus.
Fine et al. (2009) identified phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (PREX2a, 612139) as a PTEN-interacting protein. PREX2a mRNA was more abundant in human cancer cells and significantly increased in tumors with wildtype PTEN that expressed an activated mutant of PIK3CA encoding the p110 subunit of phosphoinositide 3-kinase subunit alpha (PI3K-alpha). PREX2a inhibited PTEN lipid phosphatase activity and stimulated the PI3K pathway only in the presence of PTEN. PREX2a stimulated cell growth and cooperated with a PIK3CA mutant to promote growth factor-independent proliferation and transformation. Depletion of PREX2a reduced amounts of phosphorylated AKT and growth in human cell lines with intact PTEN. Thus, Fine et al. (2009) concluded that PREX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells.
Teresi et al. (2008) showed that SREBP (see 184756) induced PTEN protein expression in MCF-7 cells via upregulation of PPAR-gamma (PPARG; 601487). Several statins also induced both PTEN mRNA and protein and PPARG activity. However, while SREBP used PPARG transcriptional activity to upregulate PTEN expression, the statins appeared to regulate PPARG protein activity, resulting in upregulation of PTEN expression.
Sathaliyawala et al. (2010) found that the Mtor inhibitor rapamycin impaired mouse Flt3l (FLT3LG; 600007)-driven dendritic cell (DC) development in vitro, with plasmacytoid DCs and classical DCs most profoundly affected. Depletion of the Pi3k-Mtor negative regulator Pten facilitated Flt3l-driven DC development in culture. Targeting Pten in DCs in vivo caused expansion of Cd8 (see 186910)-positive and Cd103 (ITGAE; 604682)-positive classical DCs, which could be reversed by rapamycin. Increased Cd8-positive classical DC numbers caused by Pten deletion correlated with increased susceptibility to Listeria infection. Sathaliyawala et al. (2010) concluded that PI3K-MTOR signaling downstream of FLT3L controls DC development, and that restriction by PTEN ensures optimal DC numbers and subset composition.
Ning et al. (2010) found that PTEN protein was enriched in cell bodies and axon terminals of purified motor neurons. PTEN depletion led to an increase in growth cone size, promotion of axonal elongation, and increased survival. These changes were associated with alterations in downstream signaling pathways for local protein synthesis as revealed by increases in activated AKT (164730) and p70S6 (see 608938). PTEN depletion also restored beta-actin (102630) protein levels in axonal growth cones of SMN (600354)-deficient motor neurons. A single injection of adeno-associated virus serotype 6 (AAV6) expressing small interfering RNA against PTEN (siPTEN) into hind limb muscles at postnatal day 1 in SMN-delta-7 mice led to a significant PTEN depletion and robust improvement in motor neuron survival.
Deletion of either PTEN or SOCS3 (604176) in adult retinal ganglion cells (RGCs) individually promotes significant optic nerve regeneration, but regrowth tapers off around 2 weeks after crush injury (Park et al., 2008; Smith et al., 2009). Sun et al. (2011) showed that, remarkably, simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. Sun et al. (2011) further showed that PTEN and SOCS3 regulate 2 independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggested that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiologic level after injury. Sun et al. (2011) concluded that their results revealed concurrent activation of mTOR (601231) and STAT3 (102582) pathways as key for sustaining long-distance axon regeneration in adult central nervous system, a crucial step towards functional recovery.
Using tandem affinity purification, followed by mass spectrometric analysis, Kim et al. (2011) identified ribonuclease inhibitor-1 (RNH1; 173320) as a protein that interacted with PTEN in HEK293 cells. Kim et al. (2011) also found that RNH1 accelerated nuclear Drosha (RNASEN; 608828)-dependent processing of the microRNA-21 (MIR21; 611020) primary transcript (pri-MIR21) to the precursor stem-loop structure (pre-MIR21). Interaction of PTEN with RNH1 prevented interaction of RNH1 with Drosha and reduced pri-MIR21 processing in vitro and in HEK293 cells. Kim et al. (2011) concluded that PTEN tumor suppressor activity may, in part, be due to inhibited processing of MIR21, which can function as an oncogene.
Signer et al. (2014) compared protein synthesis in hematopoietic stem cells (HSCs) and restricted hematopoietic progenitors. Signer et al. (2014) found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other hematopoietic cells, even if differences in cell cycle status were controlled for or HSCs were forced to undergo self-renewing divisions. Reduced ribosome function in Rpl24 'belly spot and tail' heterozygous mice (Rpl24(Bst/+); see 604180) further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24(Bst/+) cell-autonomously rescued the effects of Pten deletion in HSCs, blocking the increase in protein synthesis, restoring HSC function, and delaying leukemogenesis. Signer et al. (2014) concluded that Pten deficiency depletes HSCs and promotes leukemia partly by increasing protein synthesis, and posited that either increased or decreased protein synthesis impairs HSC function.
To determine whether continued PTEN inactivation is required to maintain malignancy, Miething et al. (2014) generated an RNA interference-based transgenic mouse model that allowed tetracycline-dependent regulation of Pten in a time- and tissue-specific manner. Postnatal Pten knockdown in the hematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukemia. Notably, reactivation of Pten mainly reduced T-cell leukemia dissemination but had little effect on tumor load in hematopoietic organs. Leukemia infiltration into the intestine was dependent on Ccr9 (604738) G protein-coupled receptor signaling, which was amplified by Pten loss. Miething et al. (2014) concluded that in the absence of PTEN, G protein-coupled receptors may have an unanticipated role in driving tumor growth and invasion in an unsupportive environment. These results further revealed that the role of PTEN loss in tumor maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.
Zhang et al. (2015) showed that both human and mouse tumor cells with normal expression of PTEN lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumor cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN mRNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumor cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of the chemokine CCL2 (158105), which recruits IBA1 (601833)-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis. Zhang et al. (2015) concluded that their findings demonstrated a remarkable plasticity of PTEN expression in metastatic tumor cells in response to different organ microenvironments, underpinning an essential role of coevolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth.
Chen et al. (2017) found that, in spite of CD4 lymphopenia, the frequency of FOXP3 (300292)-positive regulatory T cells (Tregs) found in peripheral blood and mucosa-associated lymphoid tissue (MALT) of patients with heterozygous PTEN mutations and PHTS was similar to that found in healthy controls. However, PHTS patients had increased proliferation of FOXP3-positive cells in lymphoid tissue compared with controls. There was no alteration in PI3K signaling downstream of PTEN in PHTS patients. Gene expression, immunohistochemical, and immunoprecipitation analyses showed high levels of PHLPP (609396) and NHERF1 in FOXP3-positive cells both ex vivo and in situ. Confocal microscopy demonstrated polarization of PHLPP, PTEN, and NHERF1 in FOXP3-positive Tregs at the immune synapse using supported planar lipid bilayers. Chen et al. (2017) concluded that PTEN haploinsufficiency leads to immune dysfunction but allows normal Treg cell phenotype in vivo because of the compensatory activity of PHLPP.
Zhao et al. (2017) sought to identify 'synthetic-essential' genes in cancer: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumor-suppressor deficiency. They posited that such synthetic-essential genes would be therapeutic targets in cancers that harbor specific tumor suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 (602118) as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival, and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3-beta (605004)-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the beta-TrCP (BTRC; 603482)-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 (H3K4me3; see 602810) modification to activate transcription of the protumorigenic TNF (191160)-NF-kappa-B (see 164011) gene network. Zhao et al. (2017) concluded that their study identified a novel PTEN pathway in cancer and provided a framework for the discovery of 'trackable' targets in cancers that harbor specific tumor-suppressor deficiencies.
Wang et al. (2010) showed that resveratrol inhibited androgen receptor (AR; 313700) transcriptional activity in both androgen-dependent and -independent prostate cancer cells, and that resveratrol stimulated PTEN expression through AR inhibition. In contrast, resveratrol directly bound epidermal growth factor receptor (EGFR; 131550), rapidly inhibiting EGFR phosphorylation, and resulting in decreased AKT phosphorylation in an AR-independent manner. Wang et al. (2010) proposed that resveratrol may act as potential adjunctive treatment for late-stage hormone refractory prostate cancer. They also demonstrated the mechanism by which AR regulates PTEN expression at the transcription level, indicating a direct link between a nuclear receptor and the PI3K (see PIK3A, 171834)/AKT (see AKT1, 164730) pathway.
Kuchay et al. (2017) demonstrated that FBXL2 (605652), the receptor subunit of one of the 69 human SCF ubiquitin ligase complexes, binds IP3R3 (147267) and targets it for ubiquitin-, p97 (VCP; 601023)-, and proteasome-mediated degradation to limit Ca(2+) influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knockin clones displayed increased cytosolic Ca(2+) release from the endoplasmic reticulum and sensitization to Ca(2+)-dependent apoptotic stimuli. Kuchay et al. (2017) found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten-null mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wildtype PTEN or a catalytically dead mutant stabilized IP3R3 and induced persistent Ca(2+) mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlated in human prostate cancer. Both in cell culture and xenograft models, a nondegradable IP3R3 mutant sensitized tumor cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca(2+)-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitized xenotransplanted tumors to photodynamic therapy. Kuchay et al. (2017) concluded that they identified a novel molecular mechanism that limits mitochondrial Ca(2+) overload to prevent cell death. Notably, the authors provided proof of principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.
Using immunoprecipitation followed by mass spectrometry analysis, Lee et al. (2019) identified the HECT-type E3 ubiquitin ligase WWP1 (602307) as a physical PTEN interactor and found that WWP1 specifically triggers nondegradative K27-linked polyubiquitination of PTEN to suppress its dimerization, membrane recruitment, and tumor suppressive functions both in vivo and in vitro. WWP1 is genetically amplified and frequently overexpressed in multiple cancers, including those of prostate, breast, and liver, which lead to pleiotropic inactivation of PTEN. Lee et al. (2019) found that WWP1 may be transcriptionally activated by the MYC (190080) protooncogene and that genetic depletion of Wwp1 in both Myc- driven mouse models of prostate cancer in vivo and cancer cells in vitro reactivates PTEN function, leading to inhibition of the PI3K-AKT pathway and MYC-driven tumorigenesis. Structural simulation and biochemical analyses showed that indole-3-carbinol (I3C), a derivative of cruciferous vegetables, was a natural and potent WWP1 inhibitor. Lee et al. (2019) concluded that the MYC-WWP1 axis is a fundamental and evolutionary conserved regulatory pathway for PTEN and PI3K signaling.
Regulation of PTEN Expression by PTENP1 Transcript Levels
Poliseno et al. (2010) described the functional relationship between the mRNAs produced by the PTEN tumor suppressor gene and its pseudogene PTENP1 (613531) and the critical consequences of this interaction. Poliseno et al. (2010) found that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. They also found that the PTENP1 locus is selectively lost in human cancer. Poliseno et al. (2010) extended their analysis to other cancer-related genes that possess pseudogenes, such as the oncogene KRAS (190070), and its pseudogene KRAS1P. Poliseno et al. (2010) also demonstrated that the transcripts of protein-coding genes such as PTEN are biologically active, and concluded that their findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a noncoding function for mRNAs.
Pal et al. (2012) measured insulin sensitivity and beta-cell function as well as anthropometric indices in 15 patients diagnosed with Cowden disease who carried mutations in the PTEN gene as well as 15 age-, sex-, and body mass index (BMI)-matched controls. Measures of insulin resistance were lower in patients with PTEN mutations than in controls (p = 0.001), which was confirmed by hyperinsulinemic euglycemic clamping studies. Increased AKT phosphorylation was observed in patients versus controls, suggesting that the patients' increased insulin sensitivity might be explained by enhanced insulin signaling through the PI3K/AKT pathway (see 164730). In addition, PTEN mutation carriers were obese compared to population-based controls (p less than 0.001); the increased body mass was due to augmented adiposity without corresponding changes in fat distribution. Pal et al. (2012) concluded that PTEN haploinsufficiency appears to result in an increased risk of obesity and cancer but a decreased risk of type 2 diabetes (125853), owing to enhanced insulin sensitivity.
Blumenthal and Dennis (2008) provided a detailed review of PTEN hamartoma syndromes.
Cowden Syndrome 1
Bannayan-Riley-Ruvalcaba syndrome (BRRS) was thought to be a distinct from Cowden syndrome (CWS1; 158350); however, because features of BRRS and Cowden syndrome have been found in individuals within the same family with the same PTEN mutation, they are considered to be the same disorder with variable expression and age-related penetrance (Lachlan et al., 2007).
Liaw et al. (1997) identified germline mutations in 4 of 5 families with Cowden disease (CD). They found missense (601728.0001) and nonsense (601728.0002; 601728.0003) mutations predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of the protein. Nelen et al. (1997) confirmed the PTEN gene as the Cowden disease gene in 8 unrelated families and reported germline missense mutations in CD families (e.g., 601728.0005).
Genetic heterogeneity of Cowden disease was suggested by the fact that Tsou et al. (1997) found no coding sequence mutations in 23 CD families for whom linkage to the PTEN locus had not been established. They reported 3 novel PTEN mutations in Cowden disease and demonstrated that these mutations were associated with Cowden disease and breast cancer. They found no PTEN mutations in a group of individuals with early-onset breast cancer, suggesting that germline mutations in the PTEN gene are not common in this group.
Tsou et al. (1998) found 3 mutations in the PTEN gene in unrelated individuals with Cowden disease. These included a missense mutation in exon 5, a splice site mutation in intron 7 causing exon skipping, and a missense mutation in exon 3. Tsou et al. (1998) also reported a rare polymorphism in exon 7 of the PTEN coding sequence.
Marsh et al. (1998) identified PTEN mutations in 30 of 37 (81%) Cowden disease families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion, and splice site mutations. These mutations were scattered over the entire length of PTEN, with the exception of the first, fourth, and last exons. A 'hotspot' for PTEN mutation in Cowden disease was identified in exon 5, which contains the PTPase core motif, with 13 of 30 (43%) Cowden disease mutations identified in that exon. Thus, 7 of 30 (23%) were within the core motif, the majority (5 of 7) of which were missense mutations, possibly pointing to the functional significance of this region.
Kurose et al. (1999) examined a 35-year-old Japanese man who had been followed clinically for juvenile polyposis syndrome (JPS; 174900) because of numerous hamartomatous polypoid lesions throughout the digestive tract, from esophagus to rectum. Although he had none of the pathognomonic skin lesions of Cowden disease, mutations in the PTEN gene were sought. He was found to be heterozygous for a G-to-A transition at the second nucleotide of codon 130, resulting in an arg130-to-gln (R130Q; 601728.0017) substitution. The patient's mother and sister did not carry this mutation; the father had died of brainstem infarction, a condition thought to be unrelated to Cowden disease. On closer examination of the patient, Kurose et al. (1999) found a small thyroid adenoma, a few papillomatous papules on his right hand, and a lung tumor, which was being examined for possible malignancy. Waite and Eng (2002) classified this patient as a case of Cowden disease and referred to the patient's 'classic cutaneous features.'
Trotman et al. (2007) identified lys13 and lys289 as major monoubiquitination sites essential for PTEN import. They showed that a K289E mutant protein showed normal activity and membrane association but lacked monoubiquitination at the mutated site and was excluded from nuclei. Immunohistochemical staining of intestinal polyps from a Cowden patient with the mutation revealed both nuclear and cytoplasmic PTEN staining in normal-appearing mucosa that retained wildtype PTEN; however, PTEN was excluded from the nuclei of epithelial cells that had lost the wildtype PTEN allele.
Pezzolesi et al. (2007) identified germline deletions involving the 5-prime promoter region of the PTEN gene in 4 of 30 patients with Cowden syndrome who did not have a point mutation in the coding regions of the gene. The deletions were associated with a decrease in PTEN activity and upregulation of downstream targets. The findings indicated that alterations at cis-regulatory elements can contribute to disease pathogenesis.
Lobo et al. (2009) reported that somatic colorectal carcinoma-derived PTEN missense mutations were associated with nuclear mislocalization. These mutations altered cellular proliferation, apoptosis, and anchorage-dependent growth and were found to reside in previously undescribed ATP-binding motifs (residues 60 to 73 and residues 122 to 136) in the N-terminal phosphatase domain. In contrast to wildtype PTEN, both cancer-associated somatic and germline-derived PTEN missense mutations (see, e.g., R130Q, 601728.0017) within the ATP-binding motifs resulted in mutant PTEN that did not bind ATP efficiently. The Cowden syndrome patients with germline ATP-binding motif-mutations had nuclear PTEN mislocalization. Of 4 unrelated patients with functional germline ATP-binding domain mutations, all 3 female patients had breast cancers. Lobo et al. (2009) concluded that germline and somatic mutations within PTEN ATP-binding domains may play important pathogenic roles in both heritable and sporadic carcinogenesis by PTEN nuclear mislocalization, resulting in altered signaling and growth.
In a patient referred with a diagnosis of BRRS, Arch et al. (1997) identified an interstitial deletion of 10q23.2-q24.1. They demonstrated that the PTEN gene was missing from the deleted chromosome. Because of phenotypic overlap between BRRS and Cowden disease and because of the apparent mapping to the same chromosomal area, Arch et al. (1997) proposed that Cowden disease and BRRS are allelic.
Balciuniene et al. (2007) described the patient reported by Arch et al. (1997) and 2 other patients who shared deletion of 10q22-q23 with cognitive and behavioral abnormalities. They suggested that the 10q22.3-q23.32 region should be added to the list of genomic regions affected by recurring rearrangements (612242). They related the breakpoint in each family to the organization of complex low-copy repeats (LCRs) located in the proximity of the deletions. The breakpoints in 2 of the families mapped within these LCRs, whereas the deletion in the family of Arch et al. (1997) removed the telomeric LCR and had a complex noncontiguous structure. Balciuniene et al. (2007) proposed that the LCRs in this region increased susceptibility to chromosomal rearrangements.
In studies of 2 unrelated well-characterized families with BRRS, Marsh et al. (1997) found that affected individuals demonstrated haplotype sharing for the 10q22-q23 region and screened for mutation in the PTEN gene. They identified heterozygous germline mutations: R233X (601728.0002) in one family and S170R (601728.0004) in the other family. The R233X mutation had been found in a family with classic Cowden disease by Liaw et al. (1997). The identical mutation occurred in these 2 families on 2 different 10q22-q23 haplotypes, arguing against a common ancestor or founder effect. The only common clinical features in the CD family and the BRRS family with R233X were macrocephaly and thyroid disease.
Marsh et al. (1998) identified germline PTEN mutations in 4 of 7 (57%) families with BRRS. None of these mutations was observed in the PTPase core motif.
Longy et al. (1998) identified germline PTEN mutations in 6 individuals from 4 unrelated European families with the BRRS phenotype. They noted that 4 of the 7 mutations described thus far in BRRS patients resulted in a truncated protein, and they concluded that the defect responsible for BRRS corresponds to an inactivating mutation. Longy et al. (1998) also noted that 4 mutations associated with the BRRS phenotype occur in exon 6 of PTEN, whereas 2 mutations associated with this phenotype occur in exon 7. They contrasted this with mutations associated with Cowden syndrome, where mutations in PTEN are spread over the entire gene with the exceptions of exons 1, 4, and 9.
'Proteus-like' Syndrome
Zhou et al. (2000) reported a boy with congenital hemihypertrophy, epidermoid nevi, macrocephaly, lipomas, arteriovenous malformations, and normal intellect. He was given the clinical diagnosis of 'Proteus-like' syndrome because of phenotypic similarities to Proteus syndrome (176920). Molecular analysis identified a heterozygous germline R335X mutation, and a somatic R130X (601728.0007) mutation in a nevus, lipoma, and arteriovenous malformation from the patient. The authors postulated that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Cohen et al. (2003) disputed the diagnosis of Proteus syndrome in the patient reported by Zhou et al. (2000). Cohen et al. (2003) stated that some of the clinical features were not consistent with classic Proteus syndrome and noted that the term 'Proteus-like syndrome' is unhelpful and confounding.
Loffeld et al. (2006) reported a 3-year-old boy with a germline PTEN missense mutation inherited from his mother who had Cowden syndrome. The boy showed extensive epidermal nevus, macrocephaly, vascular malformations, asymmetric hypertrophy of 1 leg, localized macrodactyly, and abdominal lipoma. They identified loss of heterozygosity for the PTEN mutation in an epidermal nevus from the boy, suggesting wildtype PTEN allele loss.
Caux et al. (2007) reported 2 unrelated families in which multiple members had typical Cowden syndrome confirmed by genetic analysis. The female proband of 1 family had an atypical phenotype of segmental overgrowth, lipomas, vascular malformations, and epidermal nevi, and molecular analysis revealed loss of the wildtype allele in several atypical lesions, including a cutaneous fibroma, an epidermal nevus, and a lipoma. The female proband of the other family also had an atypical presentation but lacked epidermal nevus, and molecular analysis of a single biopsy of her affected skin did not show loss of the wildtype PTEN allele. The findings suggested that heterozygous germline PTEN mutations associated with a mosaic inactivation of the wildtype allele may underlie multiple atypical dysmorphisms suggestive of other diseases, including 'Proteus-like' syndrome, previously reported by Zhou et al. (2000) and Loffeld et al. (2006). These atypical lesions could be explained by biallelic inactivation and complete loss of PTEN function, resulting in segmental exacerbations of the disease. To clinically distinguish between Proteus syndrome and segmental exacerbation of Cowden disease, Caux et al. (2007) suggested 'SOLAMEN syndrome' as an acronym for segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus.
Macrocephaly/Autism Syndrome
Butler et al. (2005) performed PTEN gene mutation analysis in 18 subjects with autism spectrum disorders and macrocephaly (605309). They identified germline PTEN mutations in 3 young boys: H93R (601728.0037), D252G (601728.0038), and F241S (601728.0039), respectively. There were no features suggestive of Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome except for pigmented macules on the glans penis of 1 mutation-positive boy.
Herman et al. (2007) reported 2 unrelated patients with macrocephaly/autism syndrome who each had a heterozygous mutation in the PTEN gene (601728.0007 and 601728.0040).
O'Roak et al. (2012) identified 3 heterozygous de novo mutations in the PTEN gene while sequencing 44 candidate genes among 2,446 autism spectrum disorder probands. There were 2 missense and 1 frameshift mutation identified (601728.0042-601728.0044). All 3 patients were macrocephalic.
Prostate Cancer
Deletion mapping studies based on loss of heterozygosity on 10q identified the region 10q23 to be the minimal area of loss in cases of sporadic prostate cancer. As noted earlier, the PTEN tumor suppressor gene, which was found to be inactivated by mutation in 3 prostate cancer cell lines, was isolated from this region. Cairns et al. (1997) screened 80 prostate tumors by microsatellite analysis and found chromosome 10q23 to be deleted in 23 cases. They performed a sequence analysis of the entire PTEN coding region and tested for homozygous deletion with new intragenic markers in these 23 cases with 10q23 loss of heterozygosity. In 10 of the tumors (43%) they identified the second mutation, thus establishing PTEN as a main inactivation target of 10q loss in sporadic prostate cancer.
Forrest et al. (2000) studied 188 subjects from 50 prostate cancer families in which 3 or more individuals or a sib pair with 1 diagnosed before age 67 had prostate cancer. Pairwise and multipoint linkage analysis showed no evidence of linkage to the PTEN region.
In a study of 188 probands with hereditary prostate cancer (176807), Xie et al. (2011) identified 15 different germline variants in the PTEN gene, none of which was located in an exon. However, there was no segregation of these variants with prostate cancer. There were no significant differences in the allele frequencies of 33 SNPs spanning the PTEN gene in 1,527 sporadic cases and 482 controls or in aggressive and non-aggressive cancer. Finally, an association between copy number variation involving the PTEN gene and prostate cancer was not found. Xie et al. (2011) concluded that germline variants in the PTEN gene do not have an important role in susceptibility to prostate cancer.
Breast Cancer
Shugart et al. (1999) reported linkage analysis, using markers flanking the PTEN locus, of 56 families that had 3 or more individuals with breast cancer and in whom a BRCA1 (113705) or BRCA2 (600185) mutation had not been found. Parametric and nonparametric analysis did not support linkage to the PTEN locus in these families; an overall multipoint lod score of -8.25 was obtained. Shugart et al. (1999) concluded that PTEN is not a major contributor to familial breast cancer.
Because of the association of CD with breast cancer, Figer et al. (2002) screened the 9 coding exons of the PTEN gene in 2 subsets of Israeli patients: 12 patients clinically diagnosed with BRRS, and 89 women with an apparently inherited predisposition to breast cancer, some with salient features of CD. Two of 3 familial BRRS patients exhibited novel germline mutations in PTEN and, among the 89 high-risk women, 2 mutations were detected in exon 4. The study suggested that PTEN does not play a major role in predisposing to hereditary breast cancer in Israeli women, and that detection of PTEN mutations in BRRS patients is more likely in familial cases.
Kurose et al. (2002) demonstrated high frequencies of somatic mutations in TP53 (191170) and PTEN in breast neoplastic epithelium and stroma. Mutations in TP53 and PTEN were mutually exclusive in either compartment. In contrast, mutations in WFDC1 (605322) occurred at low frequency in the stroma.
Basal-like breast cancer is a subtype of breast cancer that is highly proliferative, poorly differentiated, and has a poor prognosis. These tumor cells express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland. Saal et al. (2008) found that loss of PTEN protein expression was significantly associated with the basal-like cancer subtype in both nonhereditary breast cancer and hereditary BRCA1-deficient breast cancer. Loss of PTEN in the BRCA1-deficient basal-like breast cancer tumors was associated with frequent gross PTEN mutations, including intragenic chromosome breaks, inversions, deletions, and micro copy number alterations, consistent with a mechanism involving inappropriate repair of double-strand DNA breaks. The findings indicated a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and implied that the PTEN pathway is directly involved in transformation of basal-like progenitor cells.
Malignant Melanoma
Birck et al. (2000) analyzed the coding region of the PTEN/MMAC1 gene in uncultured specimens of malignant melanoma (155600) from 16 primary and 61 metastatic tumors from 67 patients. They found mutations in 4 of the metastatic samples (7%), and analysis of 2 intragenic polymorphisms showed allelic loss in 3 of 8 informative primary tumors (38%) and in 18 of 31 metastatic tumors (58%). One of the mutant cases showed allelic loss, suggesting that both PTEN/MMAC1 alleles were inactivated in this tumor. Birck et al. (2000) proposed that mutation and deletion of PTEN/MMAC1 may contribute to the development and progression of malignant melanoma. Celebi et al. (2000) examined 21 metastatic melanoma samples and found LOH at 10q23 in 7 of 21 samples and identified sequence alterations in the PTEN gene in 4 of the samples and sequence alterations in the p16 gene (CDKN2A; 600160) in 2 of the samples. One case showed mutations in both genes.
Wang et al. (2009) studied samples from 59 melanomas, 47 in situ and 12 invasive, from 8 patients with xeroderma pigmentosum. PTEN mutations were found in 56% of the melanomas, and 91% of the melanomas with mutations had 1 to 4 UV-type base substitutions, i.e., occurring at adjacent pyrimidines (p less than 0.0001 compared to random mutations). Almost 70% were mutations that altered amino acids, and transfection studies demonstrated that the mutations impaired PTEN function. Wang et al. (2009) stated that these data provide direct molecular evidence of UV involvement in melanoma induction in humans.
Cervical Cancer
Cervical cancer (603956) is not a known component of either Cowden syndrome or Bannayan-Zonana syndrome; however, LOH of markers on chromosome 10q is frequently observed in cervical cancers. To determine the potential role that PTEN mutation may play in cervical tumorigenesis, Kurose et al. (2000) screened 20 primary cervical cancers for LOH of polymorphic markers within and flanking the PTEN gene, and for intragenic mutations in the entire coding region and exon-intron boundaries of the PTEN gene. LOH was observed in 7 of 19 (36.8%) cases. Further, 1 sample may have had a homozygous deletion. Three (15%) intragenic mutations were found: 2 were somatic missense mutations in exon 5, which encodes the phosphatase motif, and the third was an occult germline intronic sequence variant in intron 7 that was shown to be associated with aberrant splicing. All 3 samples with the mutations also had LOH of the wildtype allele. The data indicated that disruption of PTEN by allelic loss or mutation may contribute to tumorigenesis in cervical cancers. In cervical cancer, however, unlike some other human primary carcinomas, e.g., those of the breast and thyroid, biallelic structural PTEN defects seem necessary for carcinogenesis.
Endometrial Carcinoma
Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas, irrespective of microsatellite status, and can occur in the earliest precancers. Endometrial carcinoma is the most frequent extracolonic cancer in patients with hereditary nonpolyposis colon cancer syndrome (HNPCC; see 120435), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability in component tumors. Zhou et al. (2002) obtained 41 endometrial carcinomas from 29 MLH1 (see 120436) or MSH2 (609309) mutation-positive HNPCC families and subjected them to PTEN expression and mutation analysis. Immunohistochemical analysis revealed 68% (28 of 41) of the HNPCC-related endometrial carcinomas with absent or weak PTEN expression. Mutation analysis of 20 aberrant PTEN-expressing tumors revealed that 17 (85%) harbored 18 somatic PTEN mutations. All mutations were frameshift, 10 (56%) of which involved the 6(A) tracts in exon 7 or 8. The authors suggested that PTEN may play a significant pathogenic role in both HNPCC and sporadic endometrial carcinogenesis, unlike the scenarios for colorectal cancer. They further concluded that somatic PTEN mutations, especially frameshift, may be a consequence of profound MMR deficiency in HNPCC-related endometrial carcinomas.
Uterine Leiomyosarcoma
George et al. (2017) reported a treatment-naive patient with metastatic uterine leiomyosarcoma who had experienced complete tumor remission for more than 2 years on anti-PD1 (PDCD1; 600244) monotherapy. By immunohistochemical, RNA sequencing, and whole-exome sequencing analyses, they analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue and identified biallelic PTEN loss and changes in neoantigen expression in the resistant tumor. PD1-positive cell infiltration was significantly decreased in the resistant tumor. Patient T cells responded vigorously to the neoantigens in vitro. George et al. (2017) concluded that PTEN mutations and reduced neoantigen expression are potential mediators of resistance to immune checkpoint therapy.
Squamous Cell Carcinoma, Head and Neck
Poetsch et al. (2002) studied the role of PTEN in head and neck squamous cell carcinomas (HNSCC; 275355) in correlation to mutation and methylation of the p16 gene and to previous studies concerning loss of chromosomes 9 and 10. They screened for alterations in PTEN and p16 in 52 HNSCC of different sites and found mutations in 12 (23%) tumor samples; PTEN missense mutations were found in 7 carcinomas (13%), and a loss of chromosome 10 was detected in 5 (71%) of these.
Metastatic Cancer
Robinson et al. (2017) performed whole-exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53 (191170), CDKN2A (600160), PTEN, PIK3CA (171834), and RB1 (614041). Putative pathogenic germline variants were present in 12.2% of cases, of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling.
Multiple Cancers
De Vivo et al. (2000) reported mutation analysis of the PTEN gene in 103 women drawn from 32,826 members of the prospective Nurses' Health Study cohort who had more than 1 primary tumor at different anatomic sites. They observed 2 novel germline heterozygous missense mutations in exon 5 in 5 of the cases. Neither mutation was observed in 115 controls free of diagnosed cancer. Both mutants showed partial tumor suppressor activity when compared to wildtype PTEN when transfected into a PTEN-null breast cancer cell line. The phenotype was cell-line-specific, suggesting that genetic background affects growth suppression activity of the mutants.
Reviews
Bonneau and Longy (2000) reported that 110 germline PTEN mutations had been reported in patients with 2 tumor-predisposing syndromes, with overlapping clinical features: Cowden disease and Bannayan-Riley-Ruvalcaba syndrome. A mutation hotspot is found in exon 5, which encodes the phosphatase catalytic core motif, and recurrent mutations had been found at CpG dinucleotides suggesting deamination-induced mutations. In addition to these germline mutations, they found reports of 332 somatic point mutations of PTEN, occurring in primary tumors or metastasis. These occurred particularly in endometrial carcinomas and glioblastomas. In most cases, these somatic mutations resulted in protein inactivation and, as with germline mutations, recurrent somatic mutations were found in CpG dinucleotides. A mutagenesis by insertion-deletion in repetitive elements was specifically observed in endometrial carcinomas.
Orloff and Eng (2008) provided a review of PTEN mutations and their various phenotypic effects, with emphasis on the importance of understanding PTEN-related pathways in the study of cancer genetics.
Marsh et al. (1999) screened for PTEN mutations in constitutive DNA samples from 43 individuals with Bannayan-Riley-Ruvalcaba syndrome comprising 16 sporadic and 27 familial cases, 11 of which were families with both Cowden disease and BRRS. Mutations were identified in 26 of 43 (60%) BRRS cases. Genotype-phenotype analyses within the BRRS group suggested a number of correlations, including the association of PTEN mutations and cancer or breast fibroadenoma in any given CD, BRRS, or BRRS/CD overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRRS patients (P = 0.028). In contrast to the report of Carethers et al. (1998), in which no PTEN mutations or deletions were identified in sporadic cases of BRRS, Marsh et al. (1999) found that identification of germline PTEN mutations was equally likely in sporadic and familial BRRS (P = 0.113). Comparisons between BRRS and a previously studied group of 37 CD families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CD alone or both CD and BRRS when compared with BRRS alone (P = 0.002). Among CD, BRRS, and BRRS/CD overlap families that were PTEN mutation positive, the mutation spectra appeared similar. Thus, PTEN mutation-positive CD and BRRS may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.
Zhou et al. (2003) stated that germline intragenic mutations in PTEN are associated with 80% of patients with CS and 60% of patients with BRRS; the underlying genetic causes in classic cases without a PCR-detectable PTEN mutation had not been determined. They hypothesized that gross gene deletions and mutations in the PTEN promoter might alternatively account for a subset of apparently mutation-negative patients with these 2 disorders. Using real-time and multiplex PCR techniques in 122 apparently mutation-negative patients, 95 with classic CS and 27 with BRRS, they identified 3 (11%) of 27 patients with BRRS or BBRS/CS overlap who had germline hemizygous PTEN deletions; fine mapping suggested that one deletion encompassed the whole gene (601728.0035), one included exon 1, and one encompassed exons 1-5. Analysis of the PTEN promoter revealed 9 cases (7.4%) harboring heterozygous germline mutations. All 9 had classic CS, representing almost 10% of all patients with CS studied. Eight had breast cancers and/or benign breast tumors but, otherwise, involvement of fewer than 4 organs. PTEN protein analysis, from 1 deletion-positive and 5 promoter mutation-positive samples, showed a 50% reduction in protein and multiple bands of immunoreactive protein, respectively. In contrast, control samples showed only the expected band. Furthermore, an elevated level of phosphorylated AKT was detected in the 5 promoter mutation-positive samples, compared with controls, indicating an absence of or marked reduction in functional PTEN. Zhou et al. (2003) concluded that patients with BRRS and CS without PCR-detected intragenic PTEN mutations can be offered clinical deletion analysis and promoter mutation analysis, respectively.
Eng (2003) reviewed the many syndromes related to mutation in the PTEN gene. Germline PTEN mutations had been found to occur in 80% of classic CS, 60% of BRRS, up to 20% of Proteus syndrome (176920), and approximately 50% of a 'Proteus-like' syndrome. Pooled analysis of PTEN mutation series of CS and BRRS showed that 65% of CS-associated mutations occur in the first 5 exons encoding the phosphatase domain and the promoter region, while 60% of BRRS-associated mutations occur in the 3-prime 4 exons encoding mainly the C2 domain. Somatic PTEN mutations occur with a wide distribution of frequencies in sporadic primary tumors, with the highest frequencies in endometrial carcinomas and glioblastoma multiforme.
To investigate whether all cases of Lhermitte-Duclos syndrome (LDD; see 158350), even without features of Cowden syndrome, are caused by germline PTEN mutation and whether somatic PTEN mutation occurs in sporadic LDD, Zhou et al. (2003) obtained paraffin-imbedded LDD lesions from 18 unselected, unrelated patients and performed mutational analysis of PTEN. All 15 (83%) of 18 samples were found to carry a PTEN mutation. All individuals with mutations were adult-onset patients but the 3 without mutations were diagnosed at the ages of 1, 3, and 11 years. Germline DNA was available from 6 adult-onset cases, and all germline PTEN mutations. Of these 6, 2 had Cowden syndrome features, 1 did not have Cowden syndrome features, and 3 were of unknown Cowden syndrome status. Immunohistochemistry revealed that 75% of the LDD samples had complete or partial loss of PTEN expression accompanied by elevated phosphorylated Akt, specifically in the dysplastic gangliocytoma cells. The high frequency and spectrum of germline PTEN mutations in patients ascertained by LDD alone confirmed that LDD is an important defining feature for Cowden syndrome. Individuals with LDD, even without apparent Cowden features, should be counseled as in Cowden syndrome.
Although germline PTEN mutations have been identified in a significant proportion of patients with the group of disorders referred to jointly as the 'PTEN hamartoma tumor syndrome' (PHTS), there are still many individuals with classic diagnostic features for whom mutations have not been identified. To address this, Pezzolesi et al. (2006) took a haplotype-based approach and investigated the association of specific genomic regions of the PTEN locus with PHTS. They found this locus to be characterized by 3 distinct haplotype blocks of 33 kb, 65 kb, and 43 kb. Comparisons of the haplotype distributions of all 3 blocks differed significantly among patients with PHTS and controls. 'Rare' haplotype blocks and extended haplotypes accounted for 2- to 3-fold more PHTS chromosomes than control chromosomes. PTEN mutation-negative patients were strongly associated with a haplotype block spanning a region upstream of PTEN and the gene's first intron. Furthermore, allelic combinations contributed to the phenotypic complexity of this syndrome. Taken together, these data suggested that specific haplotypes and rare alleles underlie the disease etiology in these sample populations; constitute low-penetrance, modifying loci; and, specifically in the case of patients with PHTS for whom traditional mutations have yet to be identified, may harbor pathogenic variant(s) that have escaped detection by standard PTEN mutation-scanning methods.
In a discussion of the genetics of health and the role of modifier genes in modulating the penetrance, dominance, expressivity, and pleiotropy of disease genes, Nadeau and Topol (2006) commented on the remarkable fact that the same PTEN germline mutation may result in different syndromes (see, for example, 601728.0002), suggesting that modifier genes dictate the specific cancers and developmental anomalies that occur in particular individuals, families, and populations.
Patients with Cowden syndrome with germline PTEN promoter mutations have aberrant PTEN protein expression and an increased frequency of breast cancer (Zhou et al., 2003). Teresi et al. (2007) examined the downstream effect of 5 PTEN promoter variants, including -861G/T (601728.0034) and -764G/A (601728.0033), that are not within any known cis-acting regulatory elements. Clinically, the patients with these variants had been given diagnoses of breast, thyroid, and/or endometrial cancer. Teresi et al. (2007) found that protein binding to the PTEN promoter (-893 to -755) was not altered in these variants when compared with wildtype. However, reporter assays indicated that 3 of the variants, including -861G/T and -764G/A, demonstrated a decrease of approximately 50% in luciferase activity compared with the wildtype construct. PTEN mRNA levels were not altered in these variants, whereas secondary structure predictions indicated that different PTEN 5-prime untranslated region transcript-folding patterns existed in 3 variants, suggesting an inhibition of protein translation. This was confirmed by PTEN protein analysis. These data indicated that variants causing large mRNA secondary structure alterations result in an inhibition of protein translation and a decrease in PTEN protein expression. The data emphasized the importance of PTEN promoter nucleotide variations and their ability to lead to Cowden syndrome progression by a novel regulatory mechanism. Importantly, these patients have a high prevalence of breast, thyroid, and endometrial malignancies.
Lachlan et al. (2007) were unable to find a genotype/phenotype correlation among 42 patients from 26 families with PTEN mutations and clinical features of either Cowden syndrome or BRRS. The earliest features of the PTEN-related phenotype were macrocephaly and hamartomas, with mucocutaneous features and sometimes malignancies developing over time in the same patients.
Pezzolesi et al. (2008) presented evidence that the microRNAs MIRN19A (609418) and MIRN21 (611020) may act as genetic modifiers in Cowden syndrome and its related phenotypes. MIRN19A and MIRN21 specifically target and downregulate PTEN. Among 28 PTEN mutation-positive patients carrying 1 of 3 truncating PTEN mutations (R130X, 601728.0007; R233X, 601728.0002; or R335X, 601728.0021), the authors found that variable PTEN protein levels were inversely correlated with MIRN19A and MIRN21 expression levels in patients with the R130X and/or R233X mutations. This association was not observed in those with the R335X mutation. MIR19A and MIRN21 were also differentially expressed in a series of 130 PTEN-mutation-negative patients with variable clinical phenotypes and decreased full-length PTEN protein expression. The findings indicated that differential expression of these 2 miRNAs could modulate PTEN protein levels and the Cowden syndrome and Cowden syndrome-like phenotypes, irrespective of the patient's mutation status, thus supporting their roles as genetic modifiers.
Tan et al. (2011) developed a clinical scoring system for selection of patients for PTEN mutation testing based on a prospective study of 3,042 probands satisfying relaxed Cowden syndrome clinical criteria. For adults, a semiquantitative score resulted in a well-calibrated estimation of pretest probability of PTEN status. For pediatric individuals, macrocephaly (present in 100% of patients) was a necessary criterion for PTEN testing when present with one of the following: autism or developmental delay (present in 82%); dermatologic features, including lipomas, trichilemmomas, oral papillomas, and penile freckling (present in 60%); vascular features, such as arteriovenous malformations or hemangiomas (present in 29%); or gastrointestinal polyps (present in 14%). Tan et al. (2011) noted that, in addition, pediatric-onset thyroid cancer and germ cell tumors (testicular cancer and dysgerminoma) are recognized associations of Cowden syndrome and should provoke consideration of PTEN testing.
To connect variant-specific molecular phenotypes to the clinical outcomes of individuals with PTEN variants, Mighell et al. (2020) combined 2 deep mutational scanning (DMS) datasets probing the effects of single-amino acid variation on enzyme activity and steady-state cellular abundance with the Cleveland Clinic cohort, a large, well-curated clinical cohort of PTEN variant carriers. They found that DMS data partially explained quantitative clinical traits, including head circumference and Cleveland Clinic (CC) score, which is a semiquantitative surrogate of disease burden. The authors built logistic regression models that use DMS and CADD (combined annotation-dependent depletion) scores to separate clinical PTEN variation from gnomAD control-only variation with high accuracy. Mighell et al. (2020) identified classes of DMS-defined variants with significantly different risk levels for classical hamartoma-related features (OR 4.1-102.9). In stark contrast, the risk for developing autism or developmental delay did not significantly change across variant classes (OR 5.4-12.4). The authors concluded that their findings highlighted the potential impact of combining DMS datasets with rich clinical data and provided insights that might guide personalized clinical decisions for PTEN variant carriers.
To examine the role of the dual-specificity phosphatase PTEN in ontogenesis and tumor suppression, Di Cristofano et al. (1998) disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Homozygous deficient ES (embryonic stem) cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal, and mesodermal derivatives. Heterozygous knockout mice and chimeric mice derived from heterozygous ES cells showed hyperplastic/dysplastic changes in the prostate, skin, and colon, which are characteristic of Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome. They also spontaneously developed germ cell, gonadostromal, thyroid, and colon tumors. In addition, Pten inactivation enhanced the ability of ES cells to generate tumors in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results supported the notion that PTEN haploinsufficiency plays a causal role in the 3 disorders in which mutations had been found, and demonstrated that Pten is a tumor suppressor essential for embryonic development.
Stambolic et al. (1998) found that Pten-mutant mouse embryos displayed regions of increased proliferation. In contrast, Pten-deficient immortalized mouse embryonic fibroblasts exhibited decreased sensitivity to cell death in response to a number of apoptotic stimuli, accompanied by constitutively elevated activity and phosphorylation of protein kinase B (PKB)/Akt, a crucial regulator of cell survival. Expression of exogenous Pten in mutant cells restored both their sensitivity to agonist-induced apoptosis and normal pattern of PKB/Akt phosphorylation. Furthermore, Pten negatively regulated intracellular levels of phosphatidylinositol 3,4,5-trisphosphate in cells and dephosphorylated it in vitro. These results showed that PTEN may exert its role as a tumor suppressor by negatively regulating the PI3K/PKB/Akt signaling pathway.
Di Cristofano et al. (1999) demonstrated that Pten heterozygous mutant mice develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas (134637)-deficient mutants. Fas-mediated apoptosis was impaired in Pten +/- mice, and T lymphocytes from these mice showed reduced activation-induced cell death and increased proliferation upon activation. Phosphatidylinositol 3-kinase inhibitors restored Fas responsiveness in Pten +/- mice. Di Cristofano et al. (1999) concluded that Pten is an essential mediator of the Fas response and a repressor of autoimmunity, and that their results implicated the PI3 kinase/Akt pathway in Fas-mediated apoptosis.
Inactivation of the PTEN gene and lack of p27(KIP1) expression (600778) have been detected in most advanced prostate cancers. But mice deficient for Cdkn1b, which encodes p27(Kip1), do not develop prostate cancer. PTEN activity leads to the induction of p27(KIP1) expression, which in turn can negatively regulate the transition through the cell cycle. Thus, the inactivation of p27(KIP1) may be epistatic to PTEN in the control of the cell cycle. Di Cristofano et al. (2001) showed that the concomitant inactivation of 1 Pten allele and 1 or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histologic origins. Cell proliferation, but not cell survival, is increased in mice that are heterozygous for knockout of the Pten gene and homozygous for knockout of the Cdkn1b gene. Moreover, these heterozygous/homozygous mice developed prostate carcinoma at complete penetrance within 3 months from birth. These cancers recapitulated the natural history and pathologic features of human prostate cancers. The findings reveal the crucial relevance of the combined tumor-suppressive activity of Pten and p27(Kip1) through the control of cell cycle progression.
In prostate cancer and other human malignancies, high rates of LOH are observed at the 10q23.3 region containing the human PTEN gene, but the demonstrated rate of biallelic inactivation of the PTEN gene by mutation or homozygous deletion is significantly lower than the rate of LOH. Kwabi-Addo et al. (2001) studied the transgenic adenocarcinoma of mouse prostate model and found that when these mice were bred to Pten +/- mice, haploinsufficiency of the Pten gene promoted the progression of prostate cancer. This observation may explain the discordance in rates of LOH at 10q23 and biallelic PTEN inactivation observed in prostate cancer and many other human malignancies.
Backman et al. (2001) generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mouse homozygous for this deletion developed seizures and ataxia by 9 weeks and died by 29 weeks. Histologic analysis showed brain enlargement as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt (164730). These data represented the first evidence for the role of Pten and Akt in cell size regulation in mammals and provided an animal model for a human phakomatosis condition, Lhermitte-Duclos disease.
Kwon et al. (2001) likewise investigated the function of PTEN in the brain by selective inactivation of Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human LDD. The results indicated that Pten regulates neuronal size in vivo in a cell-autonomous manner.
Groszer et al. (2001) used conditional gene targeting to mutate the mouse Pten gene only in embryonic neural stem cells. They noted enlarged, abnormal brains resulting from increased cell proliferation, decreased cell death, and enlarged cell size. The mice died shortly after birth with no signs of hydrocephalus. Analysis of isolated aggregates of neuronal progenitors (neurospheres) from these mice showed that they contained more and larger cells per sphere and that the cells displayed an increased number of cell divisions. Groszer et al. (2001) concluded that PTEN deficiency results in increased proliferation and self renewal of neural stem cells without a major disturbance of cell fate commitments. In a commentary, Penninger and Woodgett (2001) suggested that PTEN may be important for maintaining the pluripotentiality of neural and other types of stem cells and may allow for enhanced production of neuronal stem cells.
Using a high-throughput screen, Schwartzbauer and Robbins (2001) found that mouse Pten was actively translated in experimentally induced cardiac hypertrophy and that the protein level increased in the absence of increased mRNA expression. Overexpression of Pten caused apoptosis in neonatal rat primary cardiomyocytes and blocked growth factor signaling through the phosphatidylinositol 3,4,5-triphosphate pathway. Expression of a catalytically inactive Pten mutant led to cardiomyocyte hypertrophy, with increased protein synthesis, cell surface area, and atrial natriuretic factor (108780) expression. Hypertrophy was also accompanied by increased Akt activity and improved cell viability in culture.
Crackower et al. (2002) showed that cardiomyocyte-specific inactivation of Pten in mice resulted in hypertrophy and, unexpectedly, a dramatic decrease in cardiac contractility. Analysis of Pten/Pi3k-gamma double-mutant mice revealed that the cardiac hypertrophy and contractility defects could be genetically uncoupled. Pi3k-alpha (171834) was found to mediate the alteration in cell size, while Pi3k-gamma was found to act as a negative regulator of cardiac contractility. Mechanistically, Pi3k-gamma inhibited cAMP production, and hypercontractility could be reverted by blocking cAMP function. These data showed that PTEN has an important in vivo role in cardiomyocyte hypertrophy and G protein-coupled receptor signaling and identified a function for the PTEN-PI3K-gamma pathway in the modulation of heart muscle contractility.
By selective inactivation of Pten in mouse B lymphocytes and immunohistochemical analysis, Anzelon et al. (2003) detected a selective expansion of marginal zone (MZ) B and B1 cells. Pten-deficient B cells were hyperproliferative in response to mitogenic stimuli and had a lower threshold for activation through the B lymphocyte antigen receptor. Inactivation of Pten rescued germinal center, MZ B, and B1 cell formation in Cd19 (107265) -/- mice, which exhibit reduced activation of PI3K. Anzelon et al. (2003) concluded that intracellular phosphatidylinositol-3,4,5-trisphosphate has a central role in the regulation of differentiation of peripheral B-cell subsets.
Kwak et al. (2003) found that intratracheal administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA reduced bronchial inflammation and airway hyperresponsiveness in a mouse model of asthma (600807). Pi3k activity increased after allergen (ovalbumin) challenge, while Pten protein expression and activity decreased after allergen challenge. Immunoreactive Pten localized in epithelial layers around the bronchioles in control mice, but Pten staining disappeared in asthmatic lungs. PI3K inhibitors or adenovirus PTEN administration reduced the Il4 (147780), Il5 (147850), and eosinophil cationic protein (RNASE3; 131398) levels in bronchoalveolar lavage fluids. Kwak et al. (2003) concluded that PTEN may play a role in the pathogenesis of asthma.
Kwon et al. (2003) found that inhibition of Mtor (FRAP1; 601231) decreased the seizure frequency and death rate in mice with conditional Pten deficiency, prevented the increase in Pten-deficient neuronal soma size in young mice, and reversed neuronal soma enlargement in adult mice. Mtor inhibition did not decrease the size of wildtype adult neurons. Kwon et al. (2003) concluded that MTOR is required for neuronal hypertrophy downstream of PTEN deficiency, but it is not required for maintenance of normal neuronal soma size. They proposed that MTOR inhibitors may be useful therapeutic agents for the treatment of brain diseases resulting from PTEN deficiency, such as Lhermitte-Duclos disease or glioblastoma multiforme.
Backman et al. (2004) selectively inactivated Pten in murine tissues in which the MMTV-LTR (mouse mammary tumor virus long terminal repeat) promoter is active, resulting in hyperproliferation and neoplastic changes in Pten null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia that frequently progressed to focally invasive cancer. These data demonstrated that Pten is an important physiologic regulator of growth in the skin and prostate. Further, the early onset of prostatic intraepithelial neoplasia in Pten mutant males was unique to this animal model and implicated PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicated that PTEN is a critical tumor suppressor in this organ.
Horie et al. (2004) generated mice with a conditional hepatocyte-specific null mutation of the Pten gene. Mutant mice developed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, and genes involved in lipogenesis and beta-oxidation were also induced. Almost half of the mutant mice developed liver cell adenomas by 44 weeks of age; by 74 to 78 weeks of age, 100% of the livers of mutant mice showed adenomas and 66% had hepatocellular carcinomas. The mutant mice also showed insulin hypersensitivity. Horie et al. (2004) concluded that PTEN is an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.
By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, Dinulescu et al. (2005) expressed an oncogenic Kras (190070) allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma (167000); 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten, all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary.
Hamada et al. (2005) generated mice with endothelial cell-specific Pten deletion. Mutant embryos died before embryonic day 11.5 due to bleeding and cardiac failure. The phenotype was caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels and of cardiomyocytes to the endocardium. They showed that enhanced angiogenesis depended on both PI3K subunits p110-gamma (PIK3CG; 601232) and p85-alpha (PIK3R1; 171833), but that the defect in cardiovascular morphogenesis was more dependent on p110-gamma than p85-alpha. Hamada et al. (2005) concluded that interaction of PI3Ks and PTEN is essential for regulation of cardiovascular morphogenesis and postnatal neovascularization, including tumor angiogenesis.
Chen et al. (2006) demonstrated that Akt1 deficiency attenuated tumor development in Pten +/- mice.
Kwon et al. (2006) found that mice with targeted inactivation of the Pten gene in differentiated neurons of the cerebral cortex and hippocampus demonstrated abnormal social interaction and exaggerated responses to sensory stimuli. The mice also showed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axon tracts with increased synapses. The findings suggested that Pten defects in mice can result in macrocephaly and autistic-like behavior.
Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Pten generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, He et al. (2007) established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In Pten-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-AKT (164730) pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector beta-catenin (CTNNB1; 116806). AKT phosphorylates beta-catenin at ser552, resulting in a nuclear-localized form in ISCs. The observations showed that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin.
Liu et al. (2007) showed that mice with osteoblast-specific Pten deficiency were of normal size but demonstrated dramatic and progressively increasing bone mineral density throughout life. In vitro, osteoblasts lacking Pten differentiated more rapidly than controls and exhibited greatly reduced apoptosis associated with increased levels of phosphorylated Akt and activation of Akt signaling.
To assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations, Maser et al. (2007) engineered lymphoma-prone mice with chromosomal instability. Along with targeted resequencing, their comparative oncogenomic studies identified FBXW7 (606278) and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). The murine cancers acquired widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human hematopoietic, mesenchymal, and epithelial tumors. These results indicated that murine and human tumors experience common biologic processes driven by orthologous genetic events in their malignant evolution. Maser et al. (2007) concluded that the highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biologic driver events in the human oncogenome.
Reddy et al. (2008) provided genetic evidence that in mice lacking Pten in oocytes, the entire primordial follicle pool becomes activated. All primordial follicles become depleted in early adulthood, causing premature ovarian failure. Reddy et al. (2008) concluded that the mammalian oocyte serves as the headquarters of programming of follicle activation and that the oocyte PTEN-PI3K pathway governs follicle activation through control of initiation of oocyte growth.
Guo et al. (2008) showed that Pten deletion in mouse hematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T lymphoblastic leukemia (T-ALL). Self-renewable leukemia stem cells are enriched in the c-Kit(mid)CD3+Lin- compartment, where unphosphorylated beta-catenin is significantly increased. Conditional ablation of one allele of the beta-catenin gene (CTNNB1; 116806) substantially decreased the incidence and delayed the occurrence of T-ALL caused by Pten loss, indicating that activation of the beta-catenin pathway may contribute to the formation or expansion of the leukemia stem cell population. Moreover, a recurring chromosomal translocation, t(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit(mid)CD3+Lin- leukemic stem cells and CD3+ leukemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signaling were detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Guo et al. (2008) concluded that genetic or molecular alterations contribute cooperatively to leukemia stem cell transformation.
Page et al. (2009) showed that haploinsufficient Pten +/- mice were macrocephalic and that female, but not male, Pten +/- mice were impaired in social approach behavior. This phenotype was exacerbated in Pten +/- Slc6a4 (182138) +/- double-haploinsufficient mice. While increased brain size correlated with decreased sociability across these genotypes in females, within each genotype, increased brain size correlated with increased sociability, suggesting that epigenetic influences interact with genetic factors in influencing the phenotype. The findings suggested an interaction between 2 autism spectrum disorder candidate genes during brain development.
Clipperton-Allen and Page (2014) found that Pten +/- mice showed widespread brain overgrowth and deficits in social behavior. In addition, Pten +/- males showed repetitive behavior and abnormalities related to mood or anxiety, whereas Pten +/- females showed abnormal circadian activity and emotional learning. Conditional deletion of Pten in dopaminergic neurons resulted in abnormal social interactions similar to those found in Pten +/- mice. Clipperton-Allen and Page (2015) found that Pten +/- males showed reduced aggression, in addition to elevated repetitive behavior. Chen et al. (2015) found that haploinsufficiency in beta-catenin (Ctnnb1 +/-), but not Mtor, reduced cortical overgrowth in Pten +/- mice.
Alimonti et al. (2010) generated transgenic hypomorphic (hy) mice with decreasing levels of Pten expression: Pten (+/+), Pten (hy/+), Pten (+/-), and Pten (hy/-). Reduction of Pten dose in mice resulted in decreased survival, with Pten (+/-) mice showing a mean survival of 12 months and Pten (hy/-) mice showing a mean survival of about 8.5 months. Pten (hy/+) also showed decreased survival compared to wildtype. Similar to Pten (+/-) mutants, Pten (hy/+) mice had autoimmune disorders with lymphadenopathy and splenomegaly, although the onset was delayed in the Pten (hy/+) mice. Pten (hy/+), which expressed 80% of normal levels of Pten, showed increased susceptibility to tumor development compared to wildtype, with breast tumors occurring at the highest penetrance. However, tumorigenesis was not as high as in Pten (+/-) mice. Tumor size and proliferation increased with the reduction of Pten dosage. All breast tumors analyzed from Pten (hy/+) mice retained 2 intact copies of Pten and maintained Pten levels above the heterozygous levels, indicating protein expression. Cellular studies showed that subtle downregulation of Pten altered the steady-state biology of mammary tissues and the expression profiles of genes involved in cancer cell proliferation, such a cyclin B2 (CCNB2; 602755), cyclin D1 (CCND1; 168461), and Bub1 (602452). A proportion of human breast cancer tissue showed similar changes with decreased PTEN expression. Alimonti et al. (2010) proposed a continuum working model of tumorigenesis in which subtle reductions in the dose of some tumor suppressor genes may predispose to cancer development in a tissue-specific manner.
Cotter et al. (2010) showed that, in Schwann cells, mammalian discs large homolog-1 (DLG1; 601014) interacts with Pten to inhibit axonal stimulation of myelination. This mechanism limits myelin sheath thickness and prevents overmyelination in mouse sciatic nerves. Removing this brake results in myelin outfoldings and demyelination, characteristics of some peripheral neuropathies. Indeed, the Dlg1 brake is no longer functional in a mouse model of Charcot-Marie-Tooth disease (CMT4B1; 601382). Cotter et al. (2010) concluded that negative regulation of myelination appears to be essential for optimization of nerve conduction velocity and myelin maintenance.
Harrington et al. (2010) found that mice with conditional inactivation of Pten in oligodendrocytes showed hypermyelination and increased myelin sheath thickness in the corpus callosum and spinal cord during development. Older mice showed progressive axonal myelin sheath abnormalities associated with neurologic features, such as ataxia. However, there was no improvement in myelination after white matter injury in conditional Pten-knockout mice compared to control mice. The findings indicated that Pten functions to regulate myelin thickness and preserve axonal integrity in oligodendrocytes, but appears to be dispensable during myelin repair.
In a family in which 2 males had Cowden disease (CWS1; 158350) manifested by melanoma and trichilemmomas of the skin, adenocarcinoma of the breast, and glioblastoma, Liaw et al. (1997) found that the PTEN gene carried a transition at nucleotide 386, changing codon 129 from GGA (gly) to GAA (glu). In a second family in which 2 males had Cowden disease manifested by trichilemmoma and follicular adenoma of the thyroid, Liaw et al. (1997) observed the same mutation.
Ramaswamy et al. (1999) showed that PTEN protein induces a G1 block when reconstituted in PTEN-null cells. The G129E PTEN mutant, which is associated with Cowden disease, was found to have protein phosphatase activity yet was defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and failed to arrest cells in G1. These data suggested a link between induction of cell cycle block by PTEN and its ability to dephosphorylate, in vivo, phosphatidylinositol 3,4,5-triphosphate. Tumor cells lacking PTEN contained high levels of activated AKT1 (164730), suggesting that PTEN is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/AKT1 pathway.
Cowden Syndrome 1
In a family (family C) in which 3 females had Cowden disease (CWS1; 158350) manifested by trichilemmomas, multinodular goiter, and macrocephaly, Liaw et al. (1997) observed a transition in nucleotide 697, changing codon 233 from CGA (arg) to TGA (stop) (R233X), in the PTEN gene.
In a family in which members had a diagnosis of Bannayan-Riley-Ruvalcaba syndrome, reported by Gorlin et al. (1992), Marsh et al. (1997) identified the same R233X mutation that had been identified in a family by Liaw et al. (1997). The identical mutation, occurring in 2 unrelated families, arose on 2 different 10q22-q23 haplotypes, arguing against a common ancestor or founder effect. The only common clinical features in both the Cowden disease family and the family reported by Gorlin et al. (1992) with R233X were macrocephaly and thyroid disease.
Macrocephaly/Autism Syndrome
In a 3-year-old Japanese boy (P1) with macrocephaly, mental retardation, and primary immunodeficiency (605309), Tsujita et al. (2016) identified a de novo heterozygous c.697C-T transition in the PTEN gene, resulting in an R233X substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient peripheral blood cells showed decreased levels of PTEN mRNA, and activated T cells showed decreased levels of PTEN protein (about 11% of controls). Patient T and B cells showed aberrant activation of the AKT (164730)/mTOR (601231)/S6 (see 608938) pathway compared to controls. The findings were consistent with a loss of PTEN function.
In a family (family D) in which 2 males and 2 females had Cowden syndrome with Lhermitte-Duclos disease (LDD; see 158350) manifested by trichilemmomas, fibroadenoma/hamartoma of the breast, macrocephaly, and cerebellar ataxia, Liaw et al. (1997) found a transversion at nucleotide 697, converting codon 157 from GAA (glu) to TAA (stop), in the PTEN gene.
In affected members of a family with Cowden syndrome (CWS1; 158350) who were diagnosed with Bannayan-Riley-Ruvalcaba syndrome, Marsh et al. (1997) identified a mutation in exon 6 of the PTEN gene, resulting in a ser170-to-arg (S170R) substitution. Affected members of the family showed macrocephaly and speckled penis with soft tissue tumors (lipomas, hemangiomas, and leiomyomas).
In patients with Cowden syndrome (CWS1; 158350), Nelen et al. (1997) identified 3 different mutations in the PTEN gene that occurred in the active site sequence motif HCxxGxxRS/T characteristic of protein tyrosine phosphatases and dual specificity phosphatases. Two of these mutations were missense mutations, his123-to-arg and cys124-to-arg (601728.0006), and 1 was a nonsense mutation, arg130-to-ter (601728.0007), which occurred twice. All 3 could be predicted to lead to a complete or severe loss of phosphatase activity.
In patients with Cowden syndrome (CWS1; 158350), Nelen et al. (1997) identified 3 different mutations in the PTEN gene that occurred in the active site sequence motif HCxxGxxRS/T characteristic of protein tyrosine phosphatases and dual specificity phosphatases. Two of these mutations were missense mutations, cys124-to-arg and his123-to-arg (601728.0005), and 1 was a nonsense mutation, arg130-to-ter (601728.0007), which occurred twice. All 3 could be predicted to lead to a complete or severe loss of phosphatase activity.
Cowden Syndrome 1
In a study of Cowden disease (CWS1; 158350), Nelen et al. (1997) found 2 independent occurrences of an arg130-to-ter (R130X) mutation in the PTEN gene. The mutation involved a CpG dinucleotide.
Zori et al. (1998) described a family in which a mother had Cowden disease and her son had been diagnosed with Bannayan-Riley-Ruvalcaba syndrome. Both were heterozygous for the R130X mutation. The son had been seen at the age of 11 years for severe developmental delay and autistic behavior. In early childhood, rectal bleeding led to removal of a few rectal polyps; the pathology showed benign pseudopolyp with telangiectatic vessels in an inflamed myxoid stroma. His verbal and performance IQs were 40 at 11 years. He developed a goiter at 18 years for which left hemithyroidectomy was performed, and a tumor was also excised from the right side of the thyroid. The left lobe contained insular (follicular) carcinoma while the right showed nodular hyperplasia with a focus of papillary microcarcinoma. At the age of 11 years, the son had multiple pigmented macules on the glands and shaft of the penis. He lacked the second toes. The mother of the patient reported by Zori et al. (1998) had a large head (59.5 cm) and multiple small papules on her tongue and oral mucosa. She had polyposis of the entire gastrointestinal tract. Mammogram showed bilateral fibroglandular tissue with single well-defined benign nodules in each breast with mild dysplasia.
Macrocephaly/Autism Syndrome
In a 4-year-old boy with macrocephaly/autism syndrome (605309), Herman et al. (2007) identified a heterozygous R130X substitution. The substitution occurs in exon 5 of the PTEN gene within the core phosphatase domain of the protein. The child inherited the mutation from his unaffected father. Herman et al. (2007) noted that the boy may develop further clinical manifestations of other PTEN-associated syndromes and emphasized that the family was counseled on the possibility of increased tumor risk in the boy and the mutation-carrying father.
A high rate of loss of heterozygosity is observed at 10q23-q26 in endometrial carcinomas (Peiffer et al., 1995; Nagase et al., 1996; Safara et al., 1997; Peiffer-Schneider et al., 1998). Kong et al. (1997) observed 38 endometrial-cancer DNAs for LOH at loci on chromosomes 2, 9, and 10. Among 23 informative endometrial cancer samples, they found LOH in 11 (48%). PCR-SSCP analysis or direct DNA sequencing was then performed for all exons and intron-exon boundaries of the PTEN gene in 38 cancers. Whereas no mutation was found in PTEN in colorectal and pancreatic tumors, mutations were identified in 21 of the 38 endometrial carcinomas (55%). In each of 5 endometrial tumors without LOH, 2 mutations were seen. A variety of mutations were identified, including frameshifts, splice site mutations, and point mutations. Two tumors had an identical base substitution (a G-to-A transition) at the first base of intron 4. Mutations were found more often in tumors with microsatellite instability (MI+), implying that PTEN may constitute a target for microsatellite instability. Furthermore, Kong et al. (1997) suggested that the MI+ phenotype may predispose these tumors to simple base-substitution mutations, as well as to the frameshift mutations that are typical of microsatellite instability.
Olschwang et al. (1998) screened all 9 exons of PTEN by heteroduplex analysis of leukocyte genomic DNA from patients considered to have juvenile polyposis coli. In 1 patient, a T-to-G transversion at the second position of the consensus splicing donor site of exon 6 was found. This change was predicted to lead to a skipping of at least exon 6 in the processed mRNA, resulting in a shift of the translation reading frame starting at codon 164 and leading to a stop codon at position 172. The patient was a 14-year-old male who underwent colonoscopy that revealed juvenile polyposis. He had no previous personal or family history that could be related to either Cowden disease or Bannayan-Zonana syndrome. Eng and Peacocke (1998) suggested that this patient may have had Cowden syndrome (CWS1; 158350) that had not yet 'declared itself' because of reduced penetrance under 15 years of age. Waite and Eng (2002) reiterated the conclusion of Eng and Peacocke (1998) that the individuals studied by Olschwang et al. (1998) (see also 601728.0010 and 601728.0011) had Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, and stated that juvenile intestinal polyposis is not a so-called PTEN hamartoma-tumor syndrome (PHTS). They suggested that the discovery of the germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect and that such an individual should be managed medically in the same manner as all patients with PHTS.
In a patient who was considered to have juvenile polyposis coli, Olschwang et al. (1998) identified a 1-bp deletion (A) at nucleotide 696, causing a frameshift in exon 7 and leading to a stop codon at position 255. The patient was 74 years old when he presented with severe anemia and hypoalbuminemia. Gastroscopy and colonoscopy showed polyps throughout the digestive tract, which were classified as juvenile by histology, leading to the diagnosis of juvenile polyposis coli. Two years earlier, this patient had developed laryngeal cancer that was treated by radiotherapy only. This was thought to be related to heavy tobacco use and alcohol consumption. The deletion in this patient involved proline-232. Eng and Peacocke (1998) interpreted features of this patient as highly suggestive of Cowden syndrome (CWS1; 158350). Waite and Eng (2002) supported this conclusion and stated that juvenile intestinal polyposis is not a so-called PTEN hamartoma-tumor syndrome (PHTS). They suggested that the discovery of the germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect and that such an individual should be managed medically in the same manner as all patients with PHTS.
In a patient who was considered to have juvenile polyposis coli, Olschwang et al. (1998) identified a T-to-G transversion in exon 2 predicted to substitute an arginine for the methionine at codon 35. The PTEN protein demonstrates exceedingly high phylogenic conservation, with the human protein identical to that of dog and differing from that of mouse by a single amino acid change at codon 398. Codon 35 occurs in the region of PTEN that presents significant homology with tensin (600076) and auxilin. Taken together, these observations suggested that the DNA variation in this patient was deleterious. The patient underwent gastroscopy and colonoscopy at 7 years of age, after a 3-year history of intermittent rectal bleeding. Juvenile polyps were found throughout the stomach, duodenum, and colon. At the age of 10 years, clinical evaluations had not revealed any extra-digestive manifestations that could be associated with Cowden disease. Both parents underwent colonoscopy that showed normal digestive tracts. The genotypes at 8 highly polymorphic microsatellite loci in the parents and patient confirmed mendelian inheritance. Sequencing of exon 2 amplified from the DNAs of both parents revealed only codon 35 for methionine, demonstrating that codon 35 of arginine was a new mutation. Eng and Peacocke (1998) pointed out that the penetrance of Cowden syndrome (CWS1; 158350) is well under 10% below 15 years of age (Nelen et al., 1996); thus children with JPS, according to diagnostic criteria, may develop other features of Cowden syndrome as they age. Waite and Eng (2002) supported this conclusion and stated that juvenile intestinal polyposis is not a so-called PTEN hamartoma-tumor syndrome (PHTS). They suggested that the discovery of the germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect and that such an individual should be managed medically in the same manner as all patients with PHTS.
Marsh et al. (1998) studied 64 families with a Cowden syndrome-like phenotype insufficient to make the diagnosis of Cowden syndrome (CWS1; 158350). They found only 1 mutation, in a male with follicular carcinoma. The mutation was a T-to-C transition at codon 209 of the PTEN gene, resulting in a leu70-to-pro substitution predicted to affect splicing.
In 3 affected members of a family with Cowden syndrome (CWS1; 158350) who were diagnosed with Bannayan-Riley-Ruvalcaba syndrome, Longy et al. (1998) identified a 1-bp deletion (1390delC) in exon 6 of the PTEN gene, resulting in a frameshift and premature termination of the protein at codon 198. One member of the family had features more suggestive of Cowden syndrome.
Longy et al. (1998) reported a heterozygous pattern T/A for nucleotides 1338 and 1339 in exon 6 of the PTEN gene in affected members of a family with Cowden syndrome (CWS1; 158350), who had been diagnosed with Bannayan-Riley-Ruvalcaba syndrome. They interpreted this mutation as being due to a small inversion of these nucleotides, resulting in a termination signal at codon 178 (Y178X).
In a patient with Cowden syndrome-1 (CWS1; 158350) who had been diagnosed with Bannayan-Riley-Ruvalcaba syndrome, Longy et al. (1998) identified a heterozygous 144C-T transition in exon 7 of the PTEN gene, resulting in a gln214-to-ter (Q214X) substitution. Neither parent of the proband had evidence of the mutation, suggesting that it was de novo.
In a 2-year-old child with Cowden syndrome (CWS1; 158350) who had been diagnosed with Bannayan-Riley-Ruvalcaba syndrome, Longy et al. (1998) identified a de novo 1570G-T transversion in exon 7 of the PTEN gene, resulting in a glu256-to-ter (E256X) substitution. The patient also had mild psychomotor retardation.
Kurose et al. (1999) described a heterozygous G-to-A transition at the second nucleotide of codon 130 of the PTEN gene, predicted to result in an arg130-to-gln (R130Q) substitution, in a 35-year-old Japanese man who had been followed clinically for presumed juvenile polyposis syndrome because of numerous hamartomatous polypoid lesions throughout the digestive tract, from esophagus to rectum. On further examination, he was found to have a small thyroid adenoma and a few papillomatous papules on his right hand, as well as a lung tumor which had not been fully characterized at the time of report. Waite and Eng (2002) classified this patient as a case of Cowden disease (CWS1; 158350) and referred to the patient's 'classic cutaneous features.'
Cairns et al. (1997) found deletion of 10q23 in 23 of 80 prostate tumors (176807). Homozygous deletion of the PTEN gene was implicated in 6 cases by testing with new intragenic markers. Repeat sequence analysis of the coding region of the PTEN and the intron/exon boundaries in the remaining 17 prostate tumors with 10q LOH demonstrated 4 tumors with somatic mutations. One of the mutations was a 5-bp deletion involving nucleotides 761-765 in exon 7 and resulting in a frameshift. The identification of the second 'hit' in 10 (43%) of 23 tumors with LOH at 10q23 established PTEN as a main inactivation target of 10q loss in sporadic prostate cancer.
In a sporadic prostate cancer, Cairns et al. (1997) found a T-to-A transversion at nucleotide 564 in exon 6, predicted to result in a change from TAT (tyr) to TAA (stop).
In a patient with a severe form of Lhermitte-Duclos disease (LDD; 158350), Sutphen et al. (1999) identified a T-to-C transition at nucleotide 335 in the PTEN gene, resulting in a leu112-to-pro substitution. The mutation occurred in exon 5, which has been proposed to be a hotspot for PTEN germline mutations.
In affected members of a family with 2 females with phenotypic findings of Cowden syndrome (CWS1; 158350) and 2 males with phenotypic findings of Bannayan-Riley-Ruvalcaba syndrome, Celebi et al. (1999) identified a heterozygous 1003C-T transition in the PTEN gene, resulting in an arg335-to-ter (R335X) substitution. The mutation was not identified in 30 alleles from unaffected, unrelated subjects.
Zhou et al. (2000) reported a boy with congenital hemihypertrophy, epidermoid nevi, macrocephaly, lipomas, arteriovenous malformations, and normal intellect. He was given the clinical diagnosis of 'Proteus-like' syndrome because of phenotypic similarities to Proteus syndrome (176920). Molecular analysis identified a heterozygous germline R335X mutation, and a somatic R130X (601728.0007) mutation in a nevus, lipoma, and arteriovenous malformation from the patient. The authors postulated that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in 'Proteus-like' syndrome with its implications for cancer development in the future. Five unrelated patients with classic Proteus syndrome had no demonstrable mutations in PTEN. Cohen et al. (2003) disputed the diagnosis of Proteus syndrome in the patient reported by Zhou et al. (2000). Cohen et al. (2003) stated that some of the clinical features were not consistent with classic Proteus syndrome and noted that the term 'Proteus-like' syndrome is unhelpful and confounding.
Caux et al. (2007) suggested that the patient reported by Zhou et al. (2000) had segmental exacerbation of Cowden syndrome due to somatic mosaicism for a second PTEN mutation, and they suggested 'SOLAMEN syndrome' as an acronym for segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus.
In a patient with numerous manifestations of Cowden disease (CWS1; 158350) including fibroepithelial polyps and acanthosis nigricans, Raizis et al. (2000) found a single adenine insertion in exon 1 of the PTEN gene between position 40 and 41. The mutation results in a frameshift in codon 14 with protein truncation 29 amino acids later. This mutation, resulting in total disruption of the PTEN gene including the phosphatase and 5-prime tensin domain, was reported to be the most 5-prime mutation in the PTEN gene reported so far.
Marsh et al. (1998) described germline mutations in Cowden syndrome (CWS1; 158350) at the cys124 position and the gly129-to-glu (601728.0001) mutation. Families with cys124 mutations appear to have multiorgan involvement and a paucity of malignant breast disease.
Weng et al. (2001) stated that the cys124-to-ser (C124S) mutation results in a phosphatase-dead protein, with neither lipid nor protein phosphatase activity.
Celebi et al. (2000) examined 21 metastatic melanoma samples and identified a C-to-A transversion at nucleotide 633 in exon 6 of the PTEN gene, resulting in a cys211-to-ter mutation.
Celebi et al. (2000) examined 21 metastatic melanoma samples and identified a G-to-A transition at nucleotide 55 in exon 1 of the PTEN gene, resulting in an asp19-to-asn mutation.
Celebi et al. (2000) examined 21 metastatic melanoma samples and identified a G-to-A transition at nucleotide 649 in exon 7 of the PTEN gene, resulting in a val217-to-ile mutation.
Fackenthal et al. (2001) identified a 1-bp deletion in PTEN cDNA in a male with Cowden syndrome (CWS1; 158350) who developed breast cancer at the age of 41 years.
Fackenthal et al. (2001) identified a 5-bp deletion in PTEN cDNA in a family with Cowden syndrome (CWS1; 158350). One male member of this family developed breast cancer at the age of 43 years and died at the age of 57 years.
Staal et al. (2002) described a 38-year-old male who presented with focal seizures of the right arm and dysphasia in 1981. In 1985, he was found to have a meningioma (607174), which was removed completely. A low-grade glioma of the left frontal lobe was detected in 1990 and operated on in 1993 with subsequent radiotherapy. The tumor was classified as an anaplastic oligodendroglioma (GLM2; 613028). By 1998, regrowth of the tumor had occurred and the diagnosis was again anaplastic oligodendroglioma. In the patient, Staal et al. (2002) identified a heterozygous germline G-to-A transition at nucleotide 701 in exon 7 of the PTEN gene, resulting in an arg234-to-gln (R234Q) substitution, without loss of heterozygosity in tumor DNA. The mutant PTEN protein was not capable of inducing apoptosis, induced increased cell proliferation, and led to high constitutive protein kinase B (PKB, or AKT1; 164730) activation, which could not be increased further by stimulation with insulin. The patient did not show any of the clinical signs of Cowden disease (CD; 158350) or other hereditary diseases typically associated with PTEN germline mutations.
This variant, formerly titled VATER ASSOCIATION WITH MACROCEPHALY AND VENTRICULOMEGALY, has been reclassified because its contribution to the phenotype has not been confirmed.
Reardon et al. (2001) identified a de novo heterozygous his61-to-asp (H61D) mutation in the PTEN gene in a child with macrocephaly and features of VATER association (see 276950).
In a study of 52 head and neck squamous cell carcinoma tumor samples (HNSCC; 275355), Poetsch et al. (2002) found a 362C-A transition in exon 5 of the PTEN gene, resulting in an ala121-to-gly (A121G) mutation, in 1 oropharyngeal and 1 laryngeal carcinoma.
Smith et al. (2002) identified a de novo 1-bp deletion in exon 6 of the PTEN gene, 507delC, resulting in a premature stop codon (TAA) 38 nucleotides downstream within exon 6, in a 16-month-old male with features suggestive of a 'Proteus-like' syndrome (see 158350), including a left-sided epidermal nevus following the lines of Blaschko, widespread capillary venous malformation on his chest and abdomen, multiple lipoblastomata, disproportionate overgrowth of the right leg, and a progressive course. Smith et al. (2002) stated that there was clear evidence of mosaicism in this patient, although a somatic PTEN mutation was not identified in a biopsy of a skin lesion.
Cohen et al. (2003) disputed the diagnosis of Smith et al. (2002) and stated that several features in the patient had never been observed in Proteus syndrome, such as lipoblastomatosis, polypoid lesions of the jejunum and colon, and true hemangioma. Cohen et al. (2003) proposed that the patient reported by Smith et al. (2002) actually had a PTEN hamartoma tumor syndrome (CWS1; 158350).
In 9 of 97 patients with Cowden syndrome (CWS1; 158350) without a PCR-detectable PTEN mutation, Zhou et al. (2003) identified 10 heterozygous sequence variants within the PTEN promoter region, none of which was found among 186 normal white control subjects (372 chromosomes). One of the 10 variants was a -764A-G transition, present in a patient who had breast cancer but no thyroid cancer or uterine cancer. See also Teresi et al. (2007).
Zhou et al. (2003) identified a -861G-T transversion in the promoter region of the PTEN gene in a patient with Cowden syndrome (CWS1; 158350) who had breast cancer and thyroid cancer, but not uterine cancer, and showed multiorgan involvement, defined as at least 5 organs affected (Marsh et al., 1998). See also Teresi et al. (2007).
In a patient with Cowden syndrome (CWS1; 158350) who had been diagnosed with Bannayan-Riley-Ruvalcaba syndrome and in whom no PTEN mutation had been detectable by PCR, Zhou et al. (2003) identified deletion of the entire PTEN gene.
Marchese et al. (2003) described a patient with multiple granular cell tumors and phenotypic findings of Cowden syndrome (CWS1; 158350) in whom they identified a 1-bp deletion (179delG) in exon 3 of the PTEN gene, resulting in a termination sequence at codon 98. The mutation was not found in the parents, and DNA from 2 granular cell tumors and from peripheral blood of the patient showed no loss of heterozygosity. The 38-year-old Caucasian male patient, born of nonconsanguineous healthy parents, was well until the age of 16 years when blurred vision led to the diagnosis of choreoretinitis. At age 21, he underwent partial resection of the thyroid gland for microfollicular and trabecular adenoma. At the age of 22, a fibrous lesion was removed from the left turbinate sinus, as well as 3 'cystic' lesions from the left hand, which were shown to be granular cell tumors. At age 26, a parasellar angiofibroma, which was thought to have caused an arteriovenous fistula of the cavernous sinus, was removed. Cataract in the left eye was removed at the age of 28 and in the right eye at the age of 34. Diffuse gastroesophageal polyposis and multiple polyps in the rectum and sigmoid were discovered at the age of 29 years. Colonoscopy revealed multiple hyperplastic polyps (less than 100) in the descending colon sigmoid and rectum, 1 of which was, however, a schwannoma of the intestinal mucosa. A large polyp in the transverse colon was histologically interpreted as a juvenile polyp. The patient had several facial papular lesions, increased head circumference (63 cm), a left-convex scoliosis, and penile lentigines. Marchese et al. (2003) noted that although many features seen in this patient have been associated with PHTS (thyroid lesions, GI hamartomas, macrocephaly, facial papules, penile lentigines, bilateral juvenile cataracts), multiple granular cell tumors had not been described previously in patients with PHTS.
In a 4-year-old boy with macrocephaly and autistic behaviors (605309), Butler et al. (2005) identified a heterozygous A-to-G transition in exon 4 of the PTEN gene, resulting in a his93-to-arg (H93R) substitution. Preliminary protein analysis predicted an increase in the surface accessibility of the protein. Neither parent carried the mutation, and nonpaternity was excluded by microsatellite genotyping.
In a 3.5-year-old boy with macrocephaly and pervasive developmental disorder (605309), Butler et al. (2005) identified a heterozygous A-to-G transition in exon 7 of the PTEN gene, resulting in an asp252-to-gly (D252G) substitution. Preliminary protein analysis predicted an increase in the surface accessibility of the protein. The mother did not have the mutation, but the father was unavailable for mutation testing.
In a 2.5-year-old boy with macrocephaly and autistic behavior (605309), Butler et al. (2005) identified a heterozygous T-to-C transition in exon 7 of the PTEN gene, resulting in a phe241-to-ser (F241S) substitution. Preliminary protein analysis predicted a decrease in the surface accessibility of the protein. The patient, who was adopted, had freckles on his glans penis but no other cutaneous pigmentary or vascular abnormalities, and there was no known family history of Cowden syndrome (158350) or Bannayan-Riley-Ruvalcaba syndrome (see 158350). The parents were unavailable for mutation testing.
In a 27-month-old girl with macrocephaly/autism syndrome (605309), Herman et al. (2007) identified a de novo heterozygous 1-bp insertion (519insT) in exon 6 of the PTEN gene, resulting in a frameshift and premature termination at codon 179.
In a 4.5-year-old Turkish boy with verrucous epidermal nevus, macrocephaly, progressive lipomatosis, and intestinal polyposis, suggestive of Cowden syndrome (CWS1; 158350), Tekin et al. (2006) identified heterozygosity for a germline 395G-T transversion in the PTEN gene, resulting in a gly132-to-val (G132V) substitution. The mutation was not found in either parent. Loss of heterozygosity for chromosome 10q23 markers in the PTEN region was shown in tissue from a lipoma. The authors noted that the clinical presentation of this patient was similar to that of a 16-month-old boy with congenital left-sided verrucoid epidermal nevus, multiple lipoblastomas, and vascular anomalies in whom Smith et al. (2002) identified a deletion in the PTEN gene (601728.0032), but that limb overgrowth and asymmetry were absent in their patient.
In an 8-year-old non-Hispanic white female diagnosed with autism (605309), O'Roak et al. (2012) identified a heterozygous de novo thr167-to-asn (T167N) mutation in the PTEN gene. The patient had very low verbal IQ of 57, low nonverbal IQ of 77, and low adaptive score of 79. There was a history of speech delay with loss of words during development. Head circumference was 56 cm (z score = 2.8).
In a 49-month-old non-Hispanic white male diagnosed with autism (605309), O'Roak et al. (2012) identified a heterozygous de novo thr131-to-ile (T131I) mutation in the PTEN gene. The patient had very low verbal and nonverbal IQ scores of 55 and 50, respectively, with a low adaptive score of 73. There was a history of speech delay and possible nonfebrile seizures; EEG was normal. Head circumference was 57.8 cm (z score = 4.7).
In a 9-year-old non-Hispanic white male diagnosed with autism (605309), O'Roak et al. (2012) identified a heterozygous de novo insertion of 1 basepair (A) in the PTEN gene, resulting in a frameshift and premature termination of the protein (Cys136MetfsTer44). The patient had extremely low verbal IQ (19), nonverbal IQ (33), and adaptive score (57). There was a history of speech delay and loss of words during development; the patient was nonverbal at the time of the report. Head circumference was 56 cm (z score = 2.0).
In a 15-year-old Japanese girl (P2) with macrocephaly, mental retardation, and primary immunodeficiency (605309), Tsujita et al. (2016) identified a de novo heterozygous 2-bp insertion (c.41_42insGA) in the PTEN gene, resulting in a frameshift and premature termination (Arg15fsTer9). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Activated patient T cells showed decreased levels of PTEN protein (about 60% of controls). Patient T and B cells showed aberrant activation of the AKT (164730)/mTOR (601231)/S6 (see 608938) pathway compared to controls. The findings were consistent with a loss of PTEN function and increased PI3K signaling in lymphocytes.
Agrawal, S., Pilarski, R., Eng, C. Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN. Hum. Molec. Genet. 14: 2459-2468, 2005. [PubMed: 16014636] [Full Text: https://doi.org/10.1093/hmg/ddi246]
Alimonti, A., Carracedo, A., Clohessy, J. G., Trotman, L. C., Nardella, C., Egia, A., Salmena, L., Sampieri, K., Haveman, W. J., Brogi, E., Richardson, A. L., Zhang, J., Pandolfi, P. P. Subtle variations in Pten dose determine cancer susceptibility. Nature Genet. 42: 454-458, 2010. [PubMed: 20400965] [Full Text: https://doi.org/10.1038/ng.556]
Alvarez-Breckenridge, C. A., Waite, K. A., Eng, C. PTEN regulates phospholipase D and phospholipase C. Hum. Molec. Genet. 16: 1157-1163, 2007. [PubMed: 17405772] [Full Text: https://doi.org/10.1093/hmg/ddm063]
Anzelon, A. N., Wu, H., Rickert, R. C. Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nature Immun. 4: 287-294, 2003. [PubMed: 12563260] [Full Text: https://doi.org/10.1038/ni892]
Arch, E. M., Goodman, B. K., Van Wesep, R. A., Liaw, D., Clarke, K., Parsons, R., McKusick, V. A., Geraghty, M. T. Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease. Am. J. Med. Genet. 71: 489-493, 1997. [PubMed: 9286463]
Backman, S. A., Ghazarian, D., So, K., Sanchez, O., Wagner, K.-U., Hennighhausen, L., Suzuki, A., Tsao, M.-S., Chapman, W. B., Stambolic, V., Mak, T. W. Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten. Proc. Nat. Acad. Sci. 101: 1725-1730, 2004. [PubMed: 14747659] [Full Text: https://doi.org/10.1073/pnas.0308217100]
Backman, S. A., Stambolic, V., Suzuki, A., Haight, J., Elia, A., Pretorius, J., Tsao, M.-S., Shannon, P., Bolon, B., Ivy, G. O., Mak, T. W. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nature Genet. 29: 396-403, 2001. [PubMed: 11726926] [Full Text: https://doi.org/10.1038/ng782]
Balciuniene, J., Feng, N., Iyadurai, K., Hirsch, B., Charnas, L., Bill, B. R., Easterday, M. C., Staaf, J., Oseth, L., Czapansky-Beilman, D., Avramopoulos, D., Thomas, G. H., Borg, A., Valle, D., Schimmenti, L. A., Selleck, S. B. Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am. J. Hum. Genet. 80: 938-947, 2007. [PubMed: 17436248] [Full Text: https://doi.org/10.1086/513607]
Birck, A., Ahrenkiel, V., Zeuthen, J., Hou-Jensen, K., Guldberg, P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J. Invest. Derm. 114: 277-280, 2000. [PubMed: 10651986] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00877.x]
Blumenthal, G. M., Dennis, P. A. PTEN hamartoma tumor syndromes. Europ. J. Hum. Genet. 16: 1289-1300, 2008. [PubMed: 18781191] [Full Text: https://doi.org/10.1038/ejhg.2008.162]
Bonneau, D., Longy, M. Mutations of the human PTEN gene. Hum. Mutat. 16: 109-122, 2000. [PubMed: 10923032] [Full Text: https://doi.org/10.1002/1098-1004(200008)16:2<109::AID-HUMU3>3.0.CO;2-0]
Butler, M. G., Dasouki, M. J., Zhou, X.-P., Talebizadeh, Z., Brown, M. Takahashi, T. N., Miles, J. H., Wang, C. H., Stratton, R., Pilarski, R., Eng, C. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42: 318-321, 2005. [PubMed: 15805158] [Full Text: https://doi.org/10.1136/jmg.2004.024646]
Cairns, P., Okami, K., Halachmi, S., Halachmi, N., Esteller, M., Herman, J. G., Jen, J., Isaacs, W. B., Bova, G. S., Sidransky, D. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 57: 4997-5000, 1997. [PubMed: 9371490]
Cantley, L. C., Neel, B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Nat. Acad. Sci. 96: 4240-4245, 1999. [PubMed: 10200246] [Full Text: https://doi.org/10.1073/pnas.96.8.4240]
Carethers, J. M., Furnari, F. B., Zigman, A. F., Lavine, J. E., Jones, M. C., Graham, G. E., Teebi, A. S., Huang, H.-J. S., Ha, H. T., Chauhan, D. P., Chang, C. L., Cavenee, W. K., Boland, C. R. Absence of PTEN/MMAC1 germ-line mutations in sporadic Bannayan-Riley-Ruvalcaba syndrome. Cancer Res. 58: 2724-2726, 1998. [PubMed: 9661881]
Caux, F., Plauchu, H., Chibon, F., Faivre, L., Fain, O., Vabres, P., Bonnet, F., Selma, Z. B., Laroche, L., Gerard, M., Longy, M. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Europ. J. Hum. Genet. 15: 767-773, 2007. [PubMed: 17392703] [Full Text: https://doi.org/10.1038/sj.ejhg.5201823]
Celebi, J. T., Shendrik, I., Silvers, D. N., Peacocke, M. Identification of PTEN mutations in metastatic melanoma specimens. J. Med. Genet. 37: 653-657, 2000. [PubMed: 10978354] [Full Text: https://doi.org/10.1136/jmg.37.9.653]
Celebi, J. T., Tsou, H. C., Chen, F. F., Zhang, H., Ping, X. L., Lebwohl, M. G., Kezis, J., Peacocke, M. Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN. J. Med. Genet. 36: 360-364, 1999. [PubMed: 10353779]
Chen, H. H., Handel, N., Ngeow, J., Muller, J., Huhn, M., Yang, H.-T., Heindl, M., Berbers, R.-M., Hegazy, A. N., Kionke, J., Yehia, L., Sack, U., and 15 others. Immune dysregulation in patients with PTEN hamartoma tumor syndrome.: analysis of FOXP3 regulatory T cells. J. Allergy Clin. Immun. 139: 607-620, 2017. [PubMed: 27477328] [Full Text: https://doi.org/10.1016/j.jaci.2016.03.059]
Chen, M.-L., Xu, P.-Z., Peng, X., Chen, W. S., Guzman, G., Yang, X., Di Cristofano, A., Pandolfi, P. P., Hay, N. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes Dev. 20: 1569-1574, 2006. [PubMed: 16778075] [Full Text: https://doi.org/10.1101/gad.1395006]
Chen, Y., Huang, W.-C., Sejourne, J., Clipperton-Allen, A. E., Page, D. T. Pten mutations alter brain growth trajectory and allocation of cell types through elevated beta-catenin signaling. J. Neurosci. 35: 10252-10267, 2015. [PubMed: 26180201] [Full Text: https://doi.org/10.1523/JNEUROSCI.5272-14.2015]
Chen, Z., Trotman, L. C., Shaffer, D., Lin, H.-K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W., Cordon-Cardo, C., Pandolfi, P. P. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. (Letter) Nature 436: 725-730, 2005. [PubMed: 16079851] [Full Text: https://doi.org/10.1038/nature03918]
Clipperton-Allen, A. E., Page, D. T. Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests. Hum. Molec. Genet. 23: 3490-3505, 2014. [PubMed: 24497577] [Full Text: https://doi.org/10.1093/hmg/ddu057]
Clipperton-Allen, A. E., Page, D. T. Decreased aggression and increased repetitive behavior in Pten haploinsufficient mice. Genes Brain Behav. 14: 145-157, 2015. [PubMed: 25561290] [Full Text: https://doi.org/10.1111/gbb.12192]
Cohen, M. M., Jr., Turner, J. T., Biesecker, L. G. Proteus syndrome: misdiagnosis with PTEN mutations. Am. J. Med. Genet. 122A: 323-324, 2003. [PubMed: 14518070] [Full Text: https://doi.org/10.1002/ajmg.a.20474]
Cotter, L., Ozcelik, M., Jacob, C., Pereira, J. A., Locher, V., Baumann, R., Relvas, J. B., Suter, U., Tricaud, N. Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science 328: 1415-1418, 2010. [PubMed: 20448149] [Full Text: https://doi.org/10.1126/science.1187735]
Crackower, M. A., Oudit, G. Y., Kozieradzki, I., Sarao, R., Sun, H., Sasaki, T., Hirsch, E., Suzuki, A., Shioi, T., Irie-Sasaki, J., Sah, R., Cheng, H.-Y. M., and 13 others. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110: 737-749, 2002. [PubMed: 12297047] [Full Text: https://doi.org/10.1016/s0092-8674(02)00969-8]
Dahia, P. L. M., Aguiar, R. C. T., Alberta, J., Kum, J. B., Caron, S., Sill, H., Marsh, D. J., Ritz, J., Freedman, A., Stiles, C., Eng, C. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum. Molec. Genet. 8: 185-193, 1999. [PubMed: 9931326] [Full Text: https://doi.org/10.1093/hmg/8.2.185]
De Vivo, I., Gertig, D. M., Nagase, S., Hankinson, S. E., O'Brien, R., Speizer, F. E., Parsons, R., Hunter, D. J. Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers. J. Med. Genet. 37: 336-341, 2000. [PubMed: 10807691] [Full Text: https://doi.org/10.1136/jmg.37.5.336]
Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C., Pandolfi, P. P. Pten and p27(KIP1) cooperate in prostate cancer tumor suppression in the mouse. Nature Genet. 27: 222-224, 2001. [PubMed: 11175795] [Full Text: https://doi.org/10.1038/84879]
Di Cristofano, A., Kotsi, P., Peng, Y. F., Cordon-Cardo, C., Elkon, K. B., Pandolfi, P. P. Impaired Fas response and autoimmunity in Pten +/- mice. Science 285: 2122-2125, 1999. [PubMed: 10497129] [Full Text: https://doi.org/10.1126/science.285.5436.2122]
Di Cristofano, A., Pandolfi, P. P. The multiple roles of PTEN in tumor suppression. Cell 100: 387-390, 2000. [PubMed: 10693755] [Full Text: https://doi.org/10.1016/s0092-8674(00)80674-1]
Di Cristofano, A., Pesce, B., Cordon-Cardo, C., Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression. Nature Genet. 19: 348-355, 1998. [PubMed: 9697695] [Full Text: https://doi.org/10.1038/1235]
Dinulescu, D. M., Ince, T. A., Quade, B. J., Shafer, S. A., Crowley, D., Jacks, T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nature Med. 11: 63-70, 2005. [PubMed: 15619626] [Full Text: https://doi.org/10.1038/nm1173]
Drinjakovic, J., Jung, H., Campbell, D. S., Strochlic, L., Dwivedy, A., Holt, C. E. E3 ligase Nedd4 promotes axon branching by downregulating PTEN. Neuron 65: 341-357, 2010. [PubMed: 20159448] [Full Text: https://doi.org/10.1016/j.neuron.2010.01.017]
Eng, C., Peacocke, M. PTEN and inherited hamartoma-cancer syndromes. (Letter) Nature Genet. 19: 223 only, 1998. [PubMed: 9662392] [Full Text: https://doi.org/10.1038/897]
Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 22: 183-198, 2003. [PubMed: 12938083] [Full Text: https://doi.org/10.1002/humu.10257]
Fackenthal, J. D., Marsh, D. J., Richardson, A.-L., Cummings, S. A., Eng, C., Robinson, B. G., Olopade, O. I. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J. Med. Genet. 38: 159-164, 2001. [PubMed: 11238682] [Full Text: https://doi.org/10.1136/jmg.38.3.159]
Figer, A., Kaplan, A., Frydman, M., Lev, D., Paswell, J., Papa, M. Z., Goldman, B., Friedman, E. Germline mutations in the PTEN gene in Israeli patients with Bannayan-Riley-Ruvalcaba syndrome and women with familial breast cancer. Clin. Genet. 62: 298-302, 2002. [PubMed: 12372056] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.620407.x]
Fine, B., Hodakoski, C., Koujak, S., Su, T., Saal, L. H., Maurer, M., Hopkins, B., Keniry, M., Sulis, M. L., Mense, S., Hibshoosh, H., Parsons, R. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 325: 1261-1265, 2009. [PubMed: 19729658] [Full Text: https://doi.org/10.1126/science.1173569]
Forrest, M. S., Edwards, S. M., Hamoudi, R. A., Dearnaley, D. P., Arden-Jones, A., Dowe, A., Murkin, A., Kelly, J., Teare, M. D., Easton, D. F., Knowles, M. A., Bishop, D. T., Eeles, R. A., CRC/BPG UK Familial Prostate Cancer Study Collaborators, EC Biomed Familial Prostate Cancer Study Collaborators. No evidence of germline PTEN mutations in familial prostate cancer. J. Med. Genet. 37: 210-212, 2000. [PubMed: 10777362] [Full Text: https://doi.org/10.1136/jmg.37.3.210]
Funamoto, S., Meili, R., Lee, S., Parry, L., Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109: 611-623, 2002. [PubMed: 12062104] [Full Text: https://doi.org/10.1016/s0092-8674(02)00755-9]
George, S., Miao, D., Demetri, G. D., Adeegbe, D., Rodig, S. J., Shukla, S., Lipschitz, M., Amin-Mansour, A., Raut, C. P., Carter, S. L., Hammerman, P., Freeman, G. J., Wu, C. J., Ott, P. A., Wong, K.-K., Van Allen, E. M. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46: 197-204, 2017. [PubMed: 28228279] [Full Text: https://doi.org/10.1016/j.immuni.2017.02.001]
Gimm, O., Attie-Bitach, T., Lees, J. A., Vekemans, M., Eng, C. Expression of the PTEN tumour suppressor protein during human development. Hum. Molec. Genet. 9: 1633-1639, 2000. [PubMed: 10861290] [Full Text: https://doi.org/10.1093/hmg/9.11.1633]
Goberdhan, D. C. I., Wilson, C. PTEN: tumour suppressor, multifunctional growth regulator and more. Hum. Molec. Genet. 12: R239-R248, 2003. [PubMed: 12928488] [Full Text: https://doi.org/10.1093/hmg/ddg288]
Gomez-Manzano, C., Fueyo, J., Jiang, H., Glass, T. L., Lee, H.-Y., Hu, M., Liu, J.-L., Jasti, S. L., Liu, T.-J., Conrad, C. A., Yung, W. K. A. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann. Neurol. 53: 109-117, 2003. [PubMed: 12509854] [Full Text: https://doi.org/10.1002/ana.10396]
Gorlin, R. J., Cohen, M. M., Jr., Condon, L. M., Burke, B. A. Bannayan-Riley-Ruvalcaba syndrome. Am. J. Med. Genet. 44: 307-314, 1992. [PubMed: 1336932] [Full Text: https://doi.org/10.1002/ajmg.1320440309]
Groszer, M., Erickson, R., Scripture-Adams, D. D., Lesche, R., Trumpp, A., Zack, J. A., Kornblum, H. I., Liu, X., Wu, H. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294: 2186-2189, 2001. [PubMed: 11691952] [Full Text: https://doi.org/10.1126/science.1065518]
Guo, W., Lasky, J. L., Chang, C.-J., Mosessian, S., Lewis, X., Xiao, Y., Yeh, J. E., Chen, J. Y., Iruela-Arispe, M. L., Varella-Garcia, M., Wu, H. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 453: 529-533, 2008. [PubMed: 18463637] [Full Text: https://doi.org/10.1038/nature06933]
Hamada, K., Sasaki, T., Koni, P. A., Natsui, M., Kishimoto, H., Sasaki, J., Yajima, N., Horie, Y., Hasegawa, G., Naito, M., Miyazaki, J., Suda, T., Itoh, H., Nakao, K., Mak, T. W., Nakano, T., Suzuki, A. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev. 19: 2054-2065, 2005. [PubMed: 16107612] [Full Text: https://doi.org/10.1101/gad.1308805]
Hansen, G. M., Justice, M. J. Pten, a candidate tumor suppressor gene, maps to mouse chromosome 19. Mammalian Genome 9: 88-90, 1998. [PubMed: 9434957] [Full Text: https://doi.org/10.1007/s003359900690]
Harrington, E. P., Zhao, C., Fancy, S. P. J., Kaing, S., Franklin, R. J. M., Rowitch, D. H. Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination. Ann. Neurol. 68: 703-716, 2010. [PubMed: 20853437] [Full Text: https://doi.org/10.1002/ana.22090]
He, X. C., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., Dirisina, R., Porter-Westpfahl, K. S., Hembree, M., Johnson, T., Wiedemann, L. M., Barrett, T. A., Hood, L., Wu, H., Li, L. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nature Genet. 39: 189-198, 2007. [PubMed: 17237784] [Full Text: https://doi.org/10.1038/ng1928]
Herman, G. E., Butter, E., Enrile, B., Pastore, M., Prior, T. W., Sommer, A. Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am. J. Med. Genet. 143A: 589-593, 2007. [PubMed: 17286265] [Full Text: https://doi.org/10.1002/ajmg.a.31619]
Horie, Y., Suzuki, A., Kataoka, E., Sasaki, T., Hamada, K., Sasaki, J., Mizuno, K., Hasegawa, G., Kishimoto, H., Iizuka, M., Naito, M., Enomoto, K., Watanabe, S., Mak, T. W., Nakano, T. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J. Clin. Invest. 113: 1774-1783, 2004. [PubMed: 15199412] [Full Text: https://doi.org/10.1172/JCI20513]
Huang, N., Li, F., Zhang, M., Zhou, H., Chen, Z., Ma, X., Yang, L., Wu, X., Zhong, J., Xiao, F., Yang, X., Zhao, K., Li, X., Xia, X., Liu, Z., Gao, S., Zhang, N. An upstream open reading frame in phosphatase and tensin homolog encodes a circuit breaker of lactate metabolism. Cell Metab. 33: 128-144, 2021. Note: Erratum: Cell Metab. 33: 454, 2021. [PubMed: 33406399] [Full Text: https://doi.org/10.1016/j.cmet.2020.12.008]
Huse, J. T., Brennan, C., Hambardzumyan, D., Wee, B., Pena, J., Rouhanifard, S. H., Sohn-Lee, C., le Sage, C., Agami, R., Tuschl, T., Holland, E. C. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 23: 1327-1337, 2009. [PubMed: 19487573] [Full Text: https://doi.org/10.1101/gad.1777409]
Iijima, M., Devreotes, P. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109: 599-610, 2002. [PubMed: 12062103] [Full Text: https://doi.org/10.1016/s0092-8674(02)00745-6]
Kalaany, N. Y., Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458: 725-731, 2009. Note: Erratum: Nature 581: E2, 2020. [PubMed: 19279572] [Full Text: https://doi.org/10.1038/nature07782]
Kim, J. W., Kang, K. H., Burrola, P., Mak, T. W., Lemke, G. Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium. Genes Dev. 22: 3147-3157, 2008. [PubMed: 18997061] [Full Text: https://doi.org/10.1101/gad.1700108]
Kim, Y.-J., Park, S.-J., Choi, E. Y., Kim, S., Kwak, H. J., Yoo, B. C., Yoo, H., Lee, S.-H., Kim, D., Park, J. B., Kim, J. H. PTEN modulates miR-21 processing via RNA-regulatory protein RNH1. PLoS One 6: e28308, 2011. Note: Electronic Article. [PubMed: 22162762] [Full Text: https://doi.org/10.1371/journal.pone.0028308]
Kong, D., Suzuki, A., Zou, T.-T., Sakurada, A., Kemp, L. W., Wakatsuki, S., Yokoyama, T., Yamakawa, H., Furukawa, T., Sato, M., Ohuchi, N., Sato, S., Yin, J., Wang, S., Abraham, J. M., Souza, R. F., Smolinski, K. N., Meltzer, S. J., Horii, A. PTEN1 is frequently mutated in primary endometrial carcinomas. (Letter) Nature Genet. 17: 143-144, 1997. [PubMed: 9326929] [Full Text: https://doi.org/10.1038/ng1097-143]
Kuchay, S., Giorgi, C., Simoneschi, D., Pagan, J., Missiroli, S., Saraf, A., Florens, L., Washburn, M. P., Collazo-Lorduy, A., Castillo-Martin, M., Cordon-Cardo, C., Sebti, S. M., Pinton, P., Pagano, M. PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth. Nature 546: 554-558, 2017. [PubMed: 28614300] [Full Text: https://doi.org/10.1038/nature22965]
Kurose, K., Araki, T., Matsunaka, T., Takada, Y., Emi, M. Variant manifestation of Cowden disease in Japan: hamartomatous polyposis of the digestive tract with mutation of the PTEN gene. (Letter) Am. J. Hum. Genet. 64: 308-310, 1999. [PubMed: 9915974] [Full Text: https://doi.org/10.1086/302207]
Kurose, K., Gilley, K., Matsumoto, S., Watson, P. H., Zhou, X.-P., Eng, C. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature Genet. 32: 355-357, 2002. Note: Erratum: Nature Genet. 32: 681 only, 2002. [PubMed: 12379854] [Full Text: https://doi.org/10.1038/ng1013]
Kurose, K., Zhou, X.-P., Araki, T., Eng, C. Biallelic inactivating mutations and an occult germline mutation of PTEN in primary cervical carcinomas. Genes Chromosomes Cancer 29: 166-172, 2000. [PubMed: 10959096]
Kwabi-Addo, B., Giri, D., Schmidt, K., Podsypanina, K., Parsons, R., Greenberg, N., Ittmann, M. Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc. Nat. Acad. Sci. 98: 11563-11568, 2001. [PubMed: 11553783] [Full Text: https://doi.org/10.1073/pnas.201167798]
Kwak, Y.-G., Song, C. H., Yi, H. K., Hwang, P. H., Kim, J.-S., Lee, K. S., Lee, Y. C. Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma. J. Clin. Invest. 111: 1083-1092, 2003. [PubMed: 12671058] [Full Text: https://doi.org/10.1172/JCI16440]
Kwon, C.-H., Luikart, B. W., Powell, C. M., Zhou, J., Matheny, S. A., Zhang, W., Li, Y., Baker, S. J., Parada, L. F. Pten regulates neuronal arborization and social interaction in mice. Neuron 50: 377-388, 2006. [PubMed: 16675393] [Full Text: https://doi.org/10.1016/j.neuron.2006.03.023]
Kwon, C.-H., Zhu, X., Zhang, J., Baker, S. J. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc. Nat. Acad. Sci. 100: 12923-12928, 2003. [PubMed: 14534328] [Full Text: https://doi.org/10.1073/pnas.2132711100]
Kwon, C.-H., Zhu, X., Zhang, J., Knoop, L. L., Tharp, R., Smeyne, R. J., Eberhart, C. G., Burger, P. C., Baker, S. J. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nature Genet. 29: 404-411, 2001. [PubMed: 11726927] [Full Text: https://doi.org/10.1038/ng781]
Lachlan, K. L., Lucassen, A. M., Bunyan, D., Temple, I. K. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J. Med. Genet. 44: 579-585, 2007. [PubMed: 17526800] [Full Text: https://doi.org/10.1136/jmg.2007.049981]
Lee, J.-O., Yang, H., Georgescu, M.-M., Di Cristofano, A., Maehama, T., Shi, Y., Dixon, J. E., Pandolfi, P., Pavletich, N. P. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99: 323-334, 1999. [PubMed: 10555148] [Full Text: https://doi.org/10.1016/s0092-8674(00)81663-3]
Lee, Y.-R., Chen, M., Lee, J. D., Zhang, J., Lin, S.-Y., Fu, T.-M., Chen, H., Ishikawa, T., Chiang, S.-Y., Katon, J., Zhang, Y., Shulga, Y. V., and 15 others. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 364: eaau0159, 2019. Note: Electronic Article. [PubMed: 31097636] [Full Text: https://doi.org/10.1126/science.aau0159]
Li, D.-M., Sun, H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc. Nat. Acad. Sci. 95: 15406-15411, 1998. [PubMed: 9860981] [Full Text: https://doi.org/10.1073/pnas.95.26.15406]
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., Bigner, S. H., Giovanella, B. C., Ittmann, M., Tycko, B., Hibshoosh, H., Wigler, M. H., Parsons, R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943-1946, 1997. [PubMed: 9072974] [Full Text: https://doi.org/10.1126/science.275.5308.1943]
Li, L., Ernsting, B. R., Wishart, M. J., Lohse, D. L., Dixon, J. E. A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast. J. Biol. Chem. 272: 29403-29406, 1997. [PubMed: 9367992] [Full Text: https://doi.org/10.1074/jbc.272.47.29403]
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L. M., Wang, S. I., Zheng, Z., Bose, S., Call, K. M., Tsou, H. C., Peacocke, M., Eng, C., Parsons, R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16: 64-67, 1997. [PubMed: 9140396] [Full Text: https://doi.org/10.1038/ng0597-64]
Liu, X., Bruxvoort, K. J., Zylstra, C. R., Liu, J., Cichowski, R., Faugere, M.-C., Bouxsein, M. L., Wan, C., Williams, B. O., Clemens, T. L. Lifelong accumulation of bone in mice lacking Pten in osteoblasts. Proc. Nat. Acad. Sci. 104: 2259-2264, 2007. [PubMed: 17287359] [Full Text: https://doi.org/10.1073/pnas.0604153104]
Lobo, G. P., Waite, K. A., Planchon, S. M., Romigh, T., Nassif, N. T., Eng, C. Germline and somatic cancer-associated mutations in the ATP-binding motifs of PTEN influence its subcellular localization and tumor suppressive function. Hum. Molec. Genet. 18: 2851-2862, 2009. [PubMed: 19457929] [Full Text: https://doi.org/10.1093/hmg/ddp220]
Loffeld, A., McLellan, N. J., Cole, T., Payne, S. J., Fricker, D., Moss, C. Epidermal naevus in Proteus syndrome showing loss of heterozygosity for an inherited PTEN mutations. Brit. J. Derm. 154: 1194-1198, 2006. [PubMed: 16704655] [Full Text: https://doi.org/10.1111/j.1365-2133.2006.07196.x]
Longy, M., Coulon, V., Duboue, B., David, A., Larregue, M., Eng, C., Amati, P., Kraimps, J.-L., Bottani, A., Lacombe, D., Bonneau, D. Mutations of PTEN in patients with Bannayan-Riley-Ruvalcaba phenotype. J. Med. Genet. 35: 886-889, 1998. [PubMed: 9832032] [Full Text: https://doi.org/10.1136/jmg.35.11.886]
Ma, L., Chang, N., Guo, S., Li, Q., Zhang, Z., Wang, W., Tong, T. CSIG inhibits PTEN translation in replicative senescence. Molec. Cell. Biol. 28: 6290-6301, 2008. [PubMed: 18678645] [Full Text: https://doi.org/10.1128/MCB.00142-08]
Mao, J.-H., Kim, I.-J., Wu, D., Climent, J., Kang, H. C., DelRosario, R., Balmain, A. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science 321: 1499-1502, 2008. [PubMed: 18787170] [Full Text: https://doi.org/10.1126/science.1162981]
Marchese, C., Montera, M., Torrini, M., Goldoni, F., Mareni, C., Forni, M., Locatelli, L. Granular cell tumor in a PHTS patient with a novel germline PTEN mutation. (Letter) Am. J. Med. Genet. 120A: 286-288, 2003. [PubMed: 12833416] [Full Text: https://doi.org/10.1002/ajmg.a.20179]
Marsh, D. J., Coulon, V., Lunetta, K. L., Rocca-Serra, P., Dahia, P. L. M., Zheng, Z., Liaw, D., Caron, S., Duboue, B., Lin, A. Y., Richardson, A.-L., Bonnetblanc, J.-M., and 25 others. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum. Molec. Genet. 7: 507-515, 1998. [PubMed: 9467011] [Full Text: https://doi.org/10.1093/hmg/7.3.507]
Marsh, D. J., Dahia, P. L. M., Caron, S., Kum, J. B., Frayling, I. M., Tomlinson, I. P. M., Hughes, K. S., Eeles, R. A., Hodgson, S. V., Murday, V. A., Houlston, R., Eng, C. Germline PTEN mutations in Cowden syndrome-like families. J. Med. Genet. 35: 881-885, 1998. [PubMed: 9832031] [Full Text: https://doi.org/10.1136/jmg.35.11.881]
Marsh, D. J., Dahia, P. L. M., Zheng, Z., Liaw, D., Parsons, R., Gorlin, R. J., Eng, C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. (Letter) Nature Genet. 16: 333-334, 1997. [PubMed: 9241266] [Full Text: https://doi.org/10.1038/ng0897-333]
Marsh, D. J., Kum, J. B., Lunetta, K. L., Bennett, M. J., Gorlin, R. J., Ahmed, S. F., Bodurtha, J., Crowe, C., Curtis, M. A., Dasouki, M., Dunn, T., Feit, H., and 20 others. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum. Molec. Genet. 8: 1461-1472, 1999. [PubMed: 10400993] [Full Text: https://doi.org/10.1093/hmg/8.8.1461]
Martin-Belmonte, F., Gassama, A., Datta, A., Yu, W., Rescher, U., Gerke, V., Mostov, K. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128: 383-397, 2007. [PubMed: 17254974] [Full Text: https://doi.org/10.1016/j.cell.2006.11.051]
Maser, R. S., Choudhury, B., Campbell, P. J., Feng, B., Wong, K.-K., Protopopov, A., O'Neil, J., Gutierrez, A., Ivanova, E., Perna, I., Lin, E., Mani, V., and 24 others. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447: 966-971, 2007. [PubMed: 17515920] [Full Text: https://doi.org/10.1038/nature05886]
Mazurek, N., Sun, Y. J., Liu, K.-F., Gilcrease, M. Z., Schober, W., Nangia-Makker, P., Raz, A., Bresalier, R. S. Phosphorylated galectin-3 mediates tumor necrosis factor-related apoptosis-inducing ligand signaling by regulating phosphatase and tensin homologue deleted on chromosome 10 in human breast carcinoma cells. J. Biol. Chem. 282: 21337-21348, 2007. [PubMed: 17420249] [Full Text: https://doi.org/10.1074/jbc.M608810200]
Mehenni, H., Lin-Marq, N., Buchet-Poyau, K., Reymond, A., Collart, M. A., Picard, D., Antonarakis, S. E. LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum. Molec. Genet. 14: 2209-2219, 2005. [PubMed: 15987703] [Full Text: https://doi.org/10.1093/hmg/ddi225]
Miething, C., Scuoppo, C., Bosbach, B., Appelmann, I., Nakitandwe, J., Ma, J., Wu, G., Lintault, L., Auer, M., Premsrirut, P. K., Teruya-Feldstein, J., Hicks, J., Benveniste, H., Speicher, M. R., Downing, J. R., Lowe, S. W. PTEN activation in leukaemia dictated by the tissue microenvironment. Nature 510: 402-406, 2014. [PubMed: 24805236] [Full Text: https://doi.org/10.1038/nature13239]
Mighell, T. L., Thacker, S., Fombonne, E., Eng, C., O'Roak, B. J. An integrated deep-mutational-scanning approach provides clinical insights on PTEN genotype-phenotype relationships. Am. J. Hum. Genet. 106: 818-829, 2020. [PubMed: 32442409] [Full Text: https://doi.org/10.1016/j.ajhg.2020.04.014]
Modur, V., Nagarajan, R., Evers, B. M., Milbrandt, J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression: implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277: 47928-47937, 2002. [PubMed: 12351634] [Full Text: https://doi.org/10.1074/jbc.M207509200]
Mutter, G. L., Lin, M.-C., Fitzgerald, J. T., Kum, J. B., Eng, C. Changes in endometrial PTEN expression throughout the human menstrual cycle. J. Clin. Endocr. Metab. 85: 2334-2338, 2000. [PubMed: 10852473] [Full Text: https://doi.org/10.1210/jcem.85.6.6652]
Nadeau, J. H., Topol, E. J. The genetics of health. (Commentary) Nature Genet. 38: 1095-1098, 2006. [PubMed: 17006459] [Full Text: https://doi.org/10.1038/ng1006-1095]
Nagase, S., Sato, S., Tezuka, F., Wada, Y., Yajima, A., Horii, A. Deletion mapping on chromosome 10q25-q26 in human endometrial cancer. Brit. J. Cancer 74: 1979-1983, 1996. [PubMed: 8980400] [Full Text: https://doi.org/10.1038/bjc.1996.663]
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., Hortobagyi, G. N., Hung, M.-C., Yu, D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6: 117-127, 2004. [PubMed: 15324695] [Full Text: https://doi.org/10.1016/j.ccr.2004.06.022]
Nakamura, N., Ramaswamy, S., Vazquez, F., Signoretti, S., Loda, M., Sellers, W. R. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Molec. Cell. Biol. 20: 8969-8982, 2000. [PubMed: 11073996] [Full Text: https://doi.org/10.1128/MCB.20.23.8969-8982.2000]
Nelen, M. R., Padberg, G. W., Peeters, E. A., Lin, A. Y., van den Helm, B., Frants, R. R., Coulon, V., Goldstein, A. M., van Reen, M. M., Easton, D. F., Eeles, R. A., Hodgsen, S., and 10 others. Localization of the gene for Cowden disease to chromosome 10q22-23. Nature Genet. 13: 114-116, 1996. [PubMed: 8673088] [Full Text: https://doi.org/10.1038/ng0596-114]
Nelen, M. R., van Staveren, W. C. G., Peeters, E. A. J., Ben Hassel, M., Gorlin, R. J., Hamm, H., Lindboe, C. F., Fryns, J.-P., Sijmons, R. H., Woods, D. G., Mariman, E. C. M., Padberg, G. W., Kremer, H. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum. Molec. Genet. 6: 1383-1387, 1997. [PubMed: 9259288] [Full Text: https://doi.org/10.1093/hmg/6.8.1383]
Ning, K., Drepper, C., Valori, C. F., Ahsan, M., Wyles, M., Higginbottom, A., Herrmann, T., Shaw, P., Azzouz, M., Sendtner, M. PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons. Hum. Molec. Genet. 19: 3159-3168, 2010. [PubMed: 20525971] [Full Text: https://doi.org/10.1093/hmg/ddq226]
O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338: 1619-1622, 2012. [PubMed: 23160955] [Full Text: https://doi.org/10.1126/science.1227764]
Okahara, F., Ikawa, H., Kanaho, Y., Maehama, T. Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein. J. Biol. Chem. 279: 45300-45303, 2004. [PubMed: 15355975] [Full Text: https://doi.org/10.1074/jbc.C400377200]
Okumura, K., Mendoza, M., Bachoo, R. M., DePinho, R. A., Cavenee, W. K., Furnari, F. B. PCAF modulates PTEN activity. J. Biol. Chem. 281: 26562-26568, 2006. [PubMed: 16829519] [Full Text: https://doi.org/10.1074/jbc.M605391200]
Olschwang, S., Serova-Sinilnikova, O. M., Lenoir, G. M., Thomas, G. PTEN germ-line mutations in juvenile polyposis coli. (Letter) Nature Genet. 18: 12-14, 1998. [PubMed: 9425889] [Full Text: https://doi.org/10.1038/ng0198-12]
Orloff, M. S., Eng, C. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene 27: 5387-5397, 2008. [PubMed: 18794875] [Full Text: https://doi.org/10.1038/onc.2008.237]
Page, D. T., Kuti, O. J., Prestia, C., Sur, M. Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior. Proc. Nat. Acad. Sci. 106: 1989-1994, 2009. [PubMed: 19208814] [Full Text: https://doi.org/10.1073/pnas.0804428106]
Pal, A., Barber, T. M., Van de Bunt, M., Rudge, S. A., Zhang, Q., Lachlan, K. L., Cooper, N. S., Linden, H., Levy, J. C., Wakelam, M. J. O., Walker, L., Karpe, F., Gloyn, A. L. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. New Eng. J. Med. 367: 1002-1011, 2012. [PubMed: 22970944] [Full Text: https://doi.org/10.1056/NEJMoa1113966]
Palomero, T., Sulis, M. L., Cortina, M., Real, P. J., Barnes, K., Ciofani, M., Caparros, E., Buteau, J., Brown, K., Perkins, S. L., Bhagat, G., Agarwal, A. M., Basso, G., Castillo, M., Nagase, S., Cordon-Cardo, C., Parsons, R., Zuniga-Pflucker, J. C., Dominguez, M., Ferrando, A. A. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nature Med. 13: 1203-1210, 2007. [PubMed: 17873882] [Full Text: https://doi.org/10.1038/nm1636]
Pandolfi, P. P. Breast cancer--loss of PTEN predicts resistance to treatment. New Eng. J. Med. 351: 2337-2338, 2004. [PubMed: 15564551] [Full Text: https://doi.org/10.1056/NEJMcibr043143]
Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai. B., Xu, B., Connolly, L., Kramvis, I., Sahin, M., He, Z. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322: 963-966, 2008. [PubMed: 18988856] [Full Text: https://doi.org/10.1126/science.1161566]
Parsa, A. T., Waldron, J. S., Panner, A., Crane, C. A., Parney, I. F., Barry, J. J., Cachola, K. E., Murray, J. C., Tihan, T., Jensen, M. C., Mischel, P. S., Stokoe, D., Pieper, R. O. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nature Med. 13: 84-88, 2007. [PubMed: 17159987] [Full Text: https://doi.org/10.1038/nm1517]
Peiffer, S. L., Herzog, T. J., Tribune, D. J., Mutch, D. G., Gersell, D. J., Goodfellow, P. J. Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res. 55: 1922-1926, 1995. [PubMed: 7728760]
Peiffer-Schneider, S., Noonan, F. C., Mutch, D. G., Simpkins, S. B., Herzog, T., Rader, J., Elbendary, A., Gersell, D. J., Call, K., Goodfellow, P. J. Mapping an endometrial cancer tumor suppressor gene at 10q25 and development of a bacterial clone contig for the consensus deletion interval. Genomics 52: 9-16, 1998. [PubMed: 9740666] [Full Text: https://doi.org/10.1006/geno.1998.5399]
Penninger, J. M., Woodgett, J. PTEN--coupling tumor suppression to stem cells? Science 294: 2116-2118, 2001. [PubMed: 11739945] [Full Text: https://doi.org/10.1126/science.1067931]
Pezzolesi, M. G., Li, Y., Zhou, X.-P., Pilarski, R., Shen, L., Eng, C. Mutation-positive and mutation-negative patients with Cowden and Bannayan-Riley-Ruvalcaba syndromes associate with distinct 10q haplotypes. Am. J. Hum. Genet. 79: 923-934, 2006. [PubMed: 17033968] [Full Text: https://doi.org/10.1086/508943]
Pezzolesi, M. G., Platzer, P., Waite, K. A., Eng, C. Differential expression of PTEN-targeting microRNAs miR-19a and miR-21 in Cowden syndrome. Am. J. Hum. Genet. 82: 1141-1149, 2008. [PubMed: 18460397] [Full Text: https://doi.org/10.1016/j.ajhg.2008.04.005]
Pezzolesi, M. G., Zbuk, K. M., Waite, K. A., Eng, C. Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome. Hum. Molec. Genet. 16: 1058-1071, 2007. [PubMed: 17341483] [Full Text: https://doi.org/10.1093/hmg/ddm053]
Poetsch, M., Lorenz, G., Kleist, B. Detection of new PTEN/MMAC1 mutations in head and neck squamous cell carcinomas with loss of chromosome 10. Cancer Genet. Cytogenet. 132: 20-24, 2002. [PubMed: 11801303] [Full Text: https://doi.org/10.1016/s0165-4608(01)00509-x]
Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W. J., Pandolfi, P. P. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465: 1033-1038, 2010. [PubMed: 20577206] [Full Text: https://doi.org/10.1038/nature09144]
Raftopoulou, M., Etienne-Manneville, S., Self, A., Nicholls, S., Hall, A. Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science 303: 1179-1181, 2004. [PubMed: 14976311] [Full Text: https://doi.org/10.1126/science.1092089]
Raizis, A. M., Ferguson, M. M., Nicholls, D. T., Goodisson, D. W., George, P. M. A novel 5-prime (40^41insA) mutation in a patient with numerous manifestations of Cowden disease. J. Invest. Derm. 114: 597-598, 2000. [PubMed: 10777358] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.02002.x]
Ramaswamy, S., Nakamura, N., Vazquez, F., Batt, D. B., Perera, S., Roberts, T. M., Sellers, W. R. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc. Nat. Acad. Sci. 96: 2110-2115, 1999. [PubMed: 10051603] [Full Text: https://doi.org/10.1073/pnas.96.5.2110]
Reardon, W., Zhou, X.-P., Eng, C. A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. J. Med. Genet. 38: 820-823, 2001. [PubMed: 11748304] [Full Text: https://doi.org/10.1136/jmg.38.12.820]
Reddy, P., Liu, L., Adhikari, D., Jagarlamudi, K., Rajareddy, S., Shen, Y., Du, C., Tang, W., Hamalainen, T., Peng, S. L., Lan, Z.-J., Cooney, A. J., Huhtaniemi, I., Liu, K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 319: 611-613, 2008. [PubMed: 18239123] [Full Text: https://doi.org/10.1126/science.1152257]
Robinson, D. R., Wu, Y.-M., Lonigro, R. J., Vats, P., Cobain, E., Everett, J., Cao, X., Rabban, E., Kumar-Sinha, C., Raymond, V., Schuetze, S., Alva, A., and 21 others. Integrative clinical genomics of metastatic cancer. Nature 548: 297-303, 2017. [PubMed: 28783718] [Full Text: https://doi.org/10.1038/nature23306]
Saal, L. H., Gruvberger-Saal, S. K., Persson, C., Lovgren, K., Jumppanen, M., Staaf, J., Jonsson, G., Pires, M. M., Maurer, M., Holm, K., Koujak, S., Subramaniyam, S., and 13 others. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nature Genet. 40: 102-107, 2008. [PubMed: 18066063] [Full Text: https://doi.org/10.1038/ng.2007.39]
Safara, A., Maia, A. T., Martins, A. P., Roriz, M. L., Ramos, S., Leal, F., Rueff, J., Monteiro, C. A putative tumour suppressor gene DEC involved in endometrial cancer located in the q26 region of chromosome 10. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A81 only, 1997.
Sanchez, T., Thangada, S., Wu, M.-T., Kontos, C. D., Wu, D., Wu, H., Hla, T. PTEN as an effector in the signaling of antimigratory G protein-coupled receptor. Proc. Nat. Acad. Sci. 102: 4312-4317, 2005. [PubMed: 15764699] [Full Text: https://doi.org/10.1073/pnas.0409784102]
Sathaliyawala, T., O'Gorman, W. E., Greter, M., Bogunovic, M., Konjufca, V., Hou, Z. E., Nolan, G. P., Miller, M. J., Merad, M., Reizis, B. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33: 597-606, 2010. [PubMed: 20933441] [Full Text: https://doi.org/10.1016/j.immuni.2010.09.012]
Schwartzbauer, G., Robbins, J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J. Biol. Chem. 276: 35786-35793, 2001. [PubMed: 11448956] [Full Text: https://doi.org/10.1074/jbc.M102479200]
Sharrard, R. M., Maitland, N. J. Alternative splicing of the human PTEN/MMAC1/TEP1 gene. Biochim. Biophys. Acta 1494: 282-285, 2000. [PubMed: 11121587] [Full Text: https://doi.org/10.1016/s0167-4781(00)00210-4]
Shen, W. H., Balajee, A. S., Wang, J., Wu, H., Eng, C., Pandolfi, P. P., Yin, Y. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128: 157-170, 2007. [PubMed: 17218262] [Full Text: https://doi.org/10.1016/j.cell.2006.11.042]
Shugart, Y. Y., Cour, C., Renard, H., Lenoir, G., Goldgar, D., Teare, D., Easton, D., Rahman, N., Gusterton, R., Seal, S., Barfoot, R., Stratton, M., and 10 others. Linkage analysis of 56 multiplex families excludes the Cowden disease gene PTEN as a major contributor to familial breast cancer. J. Med. Genet. 36: 720-721, 1999. [PubMed: 10507734]
Signer, R. A. J., Magee, J. A., Salic, A., Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509: 49-54, 2014. [PubMed: 24670665] [Full Text: https://doi.org/10.1038/nature13035]
Smith, J. M., Kirk, E. P. E., Theodosopoulos, G., Marshall, G. M., Walker, J., Rogers, M., Field, M., Brereton, J. J., Marsh, D. J. Germline mutation of the tumour suppressor PTEN in Proteus syndrome. (Letter) J. Med. Genet. 39: 937-940, 2002. [PubMed: 12471211] [Full Text: https://doi.org/10.1136/jmg.39.12.937]
Smith, P. D., Sun, F., Park, K. K., Cai, B., Wang, C., Kuwako, K., Martinez-Carrasco, I., Connolly, L., He, Z. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64: 617-623, 2009. [PubMed: 20005819] [Full Text: https://doi.org/10.1016/j.neuron.2009.11.021]
Song, M. S., Salmena, L., Carracedo, A., Egia, A., Lo-Coco, F., Teruya-Feldstein, J., Pandolfi, P. P. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455: 813-817, 2008. [PubMed: 18716620] [Full Text: https://doi.org/10.1038/nature07290]
Staal, F. J. T., van der Luijt, R. B., Baert, M. R. M., van Drunen, J., van Bakel, H., Peters, E., de Valk, I., van Amstel, H. K. P., Taphoorn, M. J. B., Jansen, G. H., van Veelen, C. W. M., Burgering, B., Staal, G. E. J. A novel germline mutation of PTEN associated with brain tumours of multiple lineages. Brit. J. Cancer 86: 1586-1591, 2002. [PubMed: 12085208] [Full Text: https://doi.org/10.1038/sj.bjc.6600206]
Stambolic, V., MacPherson, D., Sas, D., Lin, Y., Snow, B., Jang, Y., Benchimol, S., Mak, T. W. Regulation of PTEN transcription by p53. Molec. Cell 8: 317-325, 2001. [PubMed: 11545734] [Full Text: https://doi.org/10.1016/s1097-2765(01)00323-9]
Stambolic, V., Suzuki, A., de la Pompa, J. L., Brothers, G. M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J. M., Siderovski, D. P., Mak, T. W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95: 29-39, 1998. [PubMed: 9778245] [Full Text: https://doi.org/10.1016/s0092-8674(00)81780-8]
Steck, P. A., Pershouse, M. A., Jasser, S. A., Yung, W. K. A., Lin, H., Ligon, A. H., Langford, L. A., Baumgard, M. L., Hattier, T., Davis, T., Frye, C., Hu, R., Swedlund, B., Teng, D. H. F., Tavtigian, S. V. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15: 356-362, 1997. [PubMed: 9090379] [Full Text: https://doi.org/10.1038/ng0497-356]
Sun, F., Park, K. K., Belin, S., Wang, D., Lu, T., Chen, G., Zhang, K., Yeung, C., Feng, G., Yankner, B. A., He, Z. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480: 372-375, 2011. [PubMed: 22056987] [Full Text: https://doi.org/10.1038/nature10594]
Sutphen, R., Diamond, T. M., Minton, S. E., Peacocke, M., Tsou, H. C., Root, A. W. Severe Lhermitte-Duclos disease with unique germline mutation of PTEN. Am. J. Med. Genet. 82: 290-293, 1999. [PubMed: 10051160] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990212)82:4<290::aid-ajmg3>3.0.co;2-0]
Takahashi, Y., Morales, F. C., Kreimann, E. L., Georgescu, M.-M. PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling. EMBO J. 25: 910-920, 2006. [PubMed: 16456542] [Full Text: https://doi.org/10.1038/sj.emboj.7600979]
Tamura, M., Gu, J., Matsumoto, K., Aota, S., Parsons, R., Yamada, K. M. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280: 1614-1617, 1998. [PubMed: 9616126] [Full Text: https://doi.org/10.1126/science.280.5369.1614]
Tan, M.-H., Mester, J., Peterson, C., Yang, Y., Chen, J.-L., Rybicki, L. A., Milas, K., Pederson, H., Remzi, B., Orloff, M. S., Eng, C. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am. J. Hum. Genet. 88: 42-56, 2011. [PubMed: 21194675] [Full Text: https://doi.org/10.1016/j.ajhg.2010.11.013]
Tekin, M., Hismi, B. O., Fitoz, S., Yalcinkaya, F., Ekim, M., Kansu, A., Ertem, M., Deda, G., Tutar, E., Arsan, S., Zhou, X.-P., Pilarski, R., Eng, C., Akar, N. A germline PTEN mutation with manifestations of prenatal onset and verrucous epidermal nevus. Am. J. Med. Genet. 140A: 1472-1475, 2006. [PubMed: 16752378] [Full Text: https://doi.org/10.1002/ajmg.a.31273]
Teresi, R. E., Planchon, S. M., Waite, K. A., Eng, C. Regulation of the PTEN promoter by statins and SREBP. Hum. Molec. Genet. 17: 919-928, 2008. [PubMed: 18065496] [Full Text: https://doi.org/10.1093/hmg/ddm364]
Teresi, R. E., Zbuk, K. M., Pezzolesi, M. G., Waite, K. A., Eng, C. Cowden syndrome--affected patients with PTEN promoter mutations demonstrate abnormal protein translation. Am. J. Hum. Genet. 81: 756-767, 2007. [PubMed: 17847000] [Full Text: https://doi.org/10.1086/521051]
Trotman, L. C., Wang, X., Alimont, A., Chen, Z., Teruya-Feldstein, J., Yang, H., Pavletich, N. P., Carver, B. S., Cordon-Cardo, C., Erdjument-Bromage, H., Tempst, P., Chi, S.-G., Kim, H.-J., Misteli, T., Jiang, X., Pandolfi, P. P. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141-156, 2007. [PubMed: 17218261] [Full Text: https://doi.org/10.1016/j.cell.2006.11.040]
Tsou, H. C., Ping, X. L., Xie, X. X., Gruener, A. C., Zhang, H., Nini, R., Swisshelm, K., Sybert, V., Diamond, T. M., Sutphen, R., Peacocke, M. The genetic basis of Cowden's syndrome: three novel mutations in PTEN/MMAC1/TEP1. Hum. Genet. 102: 467-473, 1998. [PubMed: 9600246] [Full Text: https://doi.org/10.1007/s004390050723]
Tsou, H. C., Teng, D. H.-F., Ping, X. L., Brancolini, V., Davis, T., Hu, R., Xie, X. X., Gruener, A. C., Schrager, C. A., Christiano, A. M., Eng, C., Steck, P., Ott, J., Tavtigian, S. V., Peacocke, M. The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am. J. Hum. Genet. 61: 1036-1043, 1997. [PubMed: 9345101] [Full Text: https://doi.org/10.1086/301607]
Tsujita, Y., Mitsui-Sekinaka, K., Imai, K., Yeh, T.-W., Mitsuiki, N., Asano, T., Ohnishi, H., Kato, Z., Sekinaka, Y., Zaha, K., Kato, T., Okano, T., and 21 others. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J. Allergy Clin. Immun. 138: 1672-1680, 2016. [PubMed: 27426521] [Full Text: https://doi.org/10.1016/j.jaci.2016.03.055]
Valiente, M., Andres-Pons, A., Gomar, B., Torres, J., Gil, A., Tapparel, C., Antonarakis, S. E., Pulido, R. Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases. J. Biol. Chem. 280: 28936-28943, 2005. [PubMed: 15951562] [Full Text: https://doi.org/10.1074/jbc.M504761200]
Waite, K. A., Eng, C. Protean PTEN: form and function. Am. J. Hum. Genet. 70: 829-844, 2002. [PubMed: 11875759] [Full Text: https://doi.org/10.1086/340026]
Waite, K. A., Eng, C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum. Molec. Genet. 12: 679-684, 2003. [PubMed: 12620973]
Waite, K. A., Sinden, M. R., Eng, C. Phytoestrogen exposure elevates PTEN levels. Hum. Molec. Genet. 14: 1457-1463, 2005. [PubMed: 15829497] [Full Text: https://doi.org/10.1093/hmg/ddi155]
Wang, X., Trotman, L. C., Koppie, T., Alimonti, A., Chen, Z., Gao, Z., Wang, J., Erdjument-Bromage, H., Tempst, P., Cordon-Cardo, C., Pandolfi, P. P., Jiang, X. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129-139, 2007. [PubMed: 17218260] [Full Text: https://doi.org/10.1016/j.cell.2006.11.039]
Wang, Y., DiGiovanna, J. J., Stern, J. B., Hornyak, T. J., Raffeld, M., Khan, S. G., Oh, K.-S., Hollander, M. C., Dennis, P. A., Kraemer, K. H. Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. Proc. Nat. Acad. Sci. 106: 6279-6284, 2009. [PubMed: 19329485] [Full Text: https://doi.org/10.1073/pnas.0812401106]
Wang, Y., Romigh, T., He, X., Orloff, M. S., Silverman, R. H., Heston, W. D., Eng, C. Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines. Hum. Molec. Genet. 19: 4319-4329, 2010. [PubMed: 20729295] [Full Text: https://doi.org/10.1093/hmg/ddq354]
Wen, S., Stolarov, J., Myers, M. P., Su, J. D., Wigler, M. H., Tonks, N. K., Durden, D. L. PTEN controls tumor-induced angiogenesis. Proc. Nat. Acad. Sci. 98: 4622-4627, 2001. [PubMed: 11274365] [Full Text: https://doi.org/10.1073/pnas.081063798]
Weng, L.-P., Brown, J. L., Baker, K. M., Ostrowski, M. C., Eng, C. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum. Molec. Genet. 11: 1687-1696, 2002. Note: Erratum: Hum. Molec. Genet. 12: 1943 only, 2003. [PubMed: 12095911] [Full Text: https://doi.org/10.1093/hmg/11.15.1687]
Weng, L.-P., Brown, J. L., Eng, C. PTEN coordinates G1 arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum. Molec. Genet. 10: 599-604, 2001. [PubMed: 11230179] [Full Text: https://doi.org/10.1093/hmg/10.6.599]
Weng, L.-P., Brown, J. L., Eng, C. PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways. Hum. Molec. Genet. 10: 237-242, 2001. [PubMed: 11159942] [Full Text: https://doi.org/10.1093/hmg/10.3.237]
Weng, L.-P., Gimm, O., Kum, J. B., Smith, W. M., Zhou, X.-P., Wynford-Thomas, D., Leone, G., Eng, C. Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death. Hum. Molec. Genet. 10: 251-258, 2001. [PubMed: 11159944] [Full Text: https://doi.org/10.1093/hmg/10.3.251]
Weng, L.-P., Smith, W. M., Brown, J. L., Eng, C. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum. Molec. Genet. 10: 605-616, 2001. [PubMed: 11230180] [Full Text: https://doi.org/10.1093/hmg/10.6.605]
Weng, L.-P., Smith, W. M., Dahia, P. L. M., Ziebold, U., Gil, E., Lees, J. A., Eng, C. PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res. 59: 5808-5814, 1999. [PubMed: 10582703]
Wishart, M. J., Taylor, G. S., Slama, J. T., Dixon, J. E. PTEN and myotubularin phosphoinositide phosphatases: bringing bioinformatics to the lab bench. Curr. Opin. Cell Biol. 13: 172-181, 2001. [PubMed: 11248551] [Full Text: https://doi.org/10.1016/s0955-0674(00)00195-2]
Wu, Y., Dowbenko, D., Spencer, S., Laura, R., Lee, J., Gu, Q., Lasky, L. A. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J. Biol. Chem. 275: 21477-21485, 2000. [PubMed: 10748157] [Full Text: https://doi.org/10.1074/jbc.M909741199]
Xie, C. C., Lu, L., Sun, J., Zheng, S. L., Isaacs, W. B., Gronberg, H., Xu, J. Germ-line sequence variants of PTEN do not have an important role in hereditary and non-hereditary prostate cancer susceptibility. J. Hum. Genet. 56: 496-502, 2011. [PubMed: 21633361] [Full Text: https://doi.org/10.1038/jhg.2011.48]
Yilmaz, O. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., Morrison, S. J. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441: 475-482, 2006. [PubMed: 16598206] [Full Text: https://doi.org/10.1038/nature04703]
Yu, Z., Fotouhi-Ardakani, N., Wu, L., Maoui, M., Wang, S., Banville, D., Shen, S.-H. PTEN associates with the vault particles in HeLa cells. J. Biol. Chem. 277: 40247-40252, 2002. [PubMed: 12177006] [Full Text: https://doi.org/10.1074/jbc.M207608200]
Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., Wu, H., Li, L. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441: 518-522, 2006. [PubMed: 16633340] [Full Text: https://doi.org/10.1038/nature04747]
Zhang, L., Zhang, S., Yao, J., Lowery, F. J., Zhang, Q., Huang, W.-C., Li, P., Li, M., Wang, X., Zhang, C., Wang, H., Ellis, K., and 10 others. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527: 100-104, 2015. [PubMed: 26479035] [Full Text: https://doi.org/10.1038/nature15376]
Zhao, D., Lu, X., Wang, G., Lan, Z., Liao, W., Li, J., Liang, X., Chen, J. R., Shah, S., Shang, X., Tang, M., Deng, P., and 9 others. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542: 484-488, 2017. [PubMed: 28166537] [Full Text: https://doi.org/10.1038/nature21357]
Zhao, M., Song, B., Pu, J., Wada, T., Reid, B., Tai, G., Wang, F., Guo, A., Walczysko, P., Gu, Y., Sasaki, T., Suzuki, A., Forrester, J. V., Bourne, H. R., Devreotes, P. N., McCaig, C. D., Penninger, J. M. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature 442: 457-460, 2006. [PubMed: 16871217] [Full Text: https://doi.org/10.1038/nature04925]
Zheng, H., Ying, H., Yan, H., Kimmelman, A. C., Hiller, D. J., Chen, A.-J., Perry, S. R., Tonon, G., Chu, G. C., Ding, Z., Stommel, J. M., Dunn, K. L., Wiedemeyer, R., You, M. J., Brennan, C., Wang, Y. A., Ligon, K. L., Wong, W. H., Chin, L., DePinho, R. A. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455: 1129-1133, 2008. [PubMed: 18948956] [Full Text: https://doi.org/10.1038/nature07443]
Zhou, X.-P., Kuismanen, S., Nystrom-Lahti, M., Peltomaki, P., Eng, C. Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. Hum. Molec. Genet. 11: 445-450, 2002. [PubMed: 11854177] [Full Text: https://doi.org/10.1093/hmg/11.4.445]
Zhou, X.-P., Marsh, D. J., Hampel, H., Mulliken, J. B., Gimm, O., Eng, C. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum. Molec. Genet. 9: 765-768, 2000. [PubMed: 10749983] [Full Text: https://doi.org/10.1093/hmg/9.5.765]
Zhou, X.-P., Marsh, D. J., Morrison, C. D., Chaudhury, A. R., Maxwell, M., Reifenberger, G., Eng, C. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am. J. Hum. Genet. 73: 1191-1198, 2003. [PubMed: 14566704] [Full Text: https://doi.org/10.1086/379382]
Zhou, X.-P., Waite, K. A., Pilarski, R., Hampel, H., Fernandez, M. J., Bos, C., Dasouki, M., Feldman, G. L., Greenberg, L. A., Ivanovich, J., Matloff, E., Patterson, A., Pierpont, M. E., Russo, D., Nassif, N. T., Eng, C. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am. J. Hum. Genet. 73: 404-411, 2003. [PubMed: 12844284] [Full Text: https://doi.org/10.1086/377109]
Zori, R. T., Marsh, D. J., Graham, G. E., Marliss, E. B., Eng, C. Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am. J. Med. Genet. 80: 399-402, 1998. [PubMed: 9856571]
Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F., Chen, E., Gottschalk, A. R., Ryan, H. E., Johnson, R. S., Jefferson, A. B., Stokoe, D., Giaccia, A. J. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14: 391-396, 2000. [PubMed: 10691731]